REVIEW LITERATURE

3. Review literature 3.1 Crystallization Crystallization is the (natural or artificial) process for the formation of solid crystals from a uniform solution. More than 80% of the substances used in pharmaceuticals, fine chemicals, agrochemicals, food and cosmetics are isolated or formulated in their solid form. Crystallization is in general the last chemical purification step in the production of Active substance ingredients. Since the properties of a solid material (polymorphism) can dramatically affect the process or the products compliance and effect (dissolution rate for example), monitoring and controlling the isolation of solids for the various applications through crystallization is of paramount interest. Crystallization is also a chemical solid-liquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs. Crystal engineering approaches, which can potentially be applied to a wide range of crystalline materials, offer an alternative and potentially fruitful method for improving the solubility, dissolution rate and subsequent bioavailability of poorly soluble drugs. The ability to engineer materials with suitable dissolution characteristics, whilst maintaining suitable physical and chemical stability provides a strong driver for the utilisation of new and existing crystal engineering approaches to drug delivery system design. The challenges of low aqueous solubility provide an ideal situation for the application of crystal engineering techniques for improving bioavailability, whilst also developing stable and robust pharmaceutical products. 9

REVIEW LITERATURE This article therefore considers the potential utility of crystal engineering as an approach for designing efficacious dosage forms for poorly soluble drugs and reviews the theory, applications, benefits and drawbacks of strategies of this type. Crystal engineering design of molecular solids in the broadest sense with the aim of tailoring specific physical or chemical properties. The diverse aspects of crystal engineering which may be used to manipulate the solubility and/or dissolution rate of the parent molecular components in the crystalline state. At the centre of these available approaches is the need to change surface and molecular assembly in equilibrium with a solution. The possible ways this may be achieved from recent developments in the study of molecular solids and reviews topical issues such as habit modification, polymorphism, solvation, co-crystal formation and surface

modification. Particular attention will be paid to the area of co-crystallization, which is an emerging area of strategic importance to the pharmaceutical sector. The fundamental concepts and principles of crystal engineering, which are typically used to control crystal size, shape and crystalline form. Although the primary focus considers the crystalline state, some reference will also be made to the utility of amorphous materials, with a brief summary of their use in enhancing drug dissolution and bioavailability. Also included are details of new and established methods, which enable precise control of crystallite size and shape and hence enable notable improvements in the dissolution rate of hydrophobic active pharmaceutical ingredients (APIs). 3.1.1 Importance crystallization technique in drug development Crystal engineering has been described as the exploitation of noncovalent interactions between molecular or ionic components for the rational design of solid10

REVIEW LITERATURE state structures that might exhibit interesting electrical, magnetic, and optical properties. It is also recognised that it is becoming increasingly evident that the specificity, directionality, and predictability of intermolecular hydrogen bonds can be utilized to assemble supramolecular structures of, at the very least, controlled dimensionality35. Supramolecular chemistry has grown around Lehn's analogy that

supermolecules are to molecules and the intermolecular bond, what molecules are to atoms and the covalent bond36. If molecules are built by connecting atoms with covalent bonds, solid-state supermolecules (crystals) are built by connecting molecules with intermolecular interactions. The fundamentals of crystal engineering were described in detail under the term molecular engineering by von Hippel in 196237. Modern crystal engineering initially began as a method for understandingthe regioselectivity and product distribution in solid-state molecular reactions, termed topochemistry38. This field has developed rapidly, particularly with the arrival of modern crystallographic techniques such as four circle diffractometers in the early 1970's followed by the introduction of area detector technology. Crystal engineering now encompasses many aspects of solid-state intermolecular interactions, structure prediction, control and rationalisation, as well as the synthesis of novel molecular building blocks and crystalline materials, and may be broken down into the components of analysis and synthesis39. Within the notion of a crystal as a supramolecular entity lies certain key ideas central to the activity of crystal engineering.

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REVIEW LITERATURE These are the nature of the crystallisation process at a molecular level, crystal packing, molecular interaction and directed molecular recognition, which will all be explored to some extent in this review and which should provide some understanding of crystal engineering approaches as a means of addressing the challenges of low aqueous solubility. 3.1.2 The crystallization process Crystallization is concerned with the evolution from solution or melt of the crystalline state. Within this area key issues include the formation of crystal nuclei, the influence of crystallization conditions, and the overlap between the concepts of the growth unit, and an understanding of how the overall shape of a crystal evolves. It is within the notion of the growth unit that a distinct link with the supramolecular concept of a synthon is achieved. The term synthon was originally introduced to describe synthetic organic structural features. The term supramolecular synthon introduced by Desiraju40 is defined as: structural units within supermolecules which can be formed and/or assembled by known conceivable synthetic operations involving intermolecular interaction. Supramolecular synthons are spatial arrangements of intermolecular interactions; the overall goal of crystal engineering is therefore to recognise and design synthons that are robust enough to be interchanged between network structures. This ensures generality ultimately leading to the predictability of one-, two- and three-dimensional patterns formed by intermolecular interactions. The Cambridge Structural Database41 may be utilized to identify stable hydrogen bonding motifs42 with the ambition that the most robust motifs will remain intact across a family of related structures.

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REVIEW LITERATURE 3.1.3 Crystal growth, crystal shape and the influence of habit modification Once nucleation has been achieved, crystal growth dominates and is the process, which leads to the evolution of embryonic crystals into a crystal form of defined size and shape. The key drivers with regard to the shape of the growing crystal are related to the crystal lattice of the molecular solids and the effects of the choice of solvent and additives on the process of crystal growth. As such, crystal growth is a layer by layer process, with the evolution of the layers being defined by the crystal packing of the unit cell. The unit cell in turn describes the critical elements of how a specific molecular species has assembled in a crystalline state in three dimensions. It is the strength of the intermolecular interaction defined within the unit cell which, at the first level, determines which layers dominate the crystal growth process. It is the case that edges or corners of a crystal are related to layers of molecules which are accompanied by dominant and directional intermolecular interaction, whereas the layer-by layer growth associated with a crystal face is related to intermolecular interactions that are less energetic in nature. A solvent or additive molecule which is able to compete for a site at an incoming point associated with the layer-by-layer growth process would be capable of disrupting the magnitude of the intermolecular interactions present between growth layers. This may then lead to a different ranking of strength of interaction between growth layers, which would manifest itself in a change in overall morphology of the crystal. Another factor is the effect of solvent or additive molecules on the growth mechanism, particularly when solubility is affected. As solubility defines super saturation, any change in supersaturation can cause the growth mechanism to move 13

REVIEW LITERATURE from screw dislocation to surface nucleation and eventually to continuous growth. This change in growth behavior has previously been discussed in the work of Burton Cabbera43 and Human44. Predicting the transition of the growth process from one of continuous growth to one of spiral growth requires details of surface diffusion, collision and exchange processes at the growth interface. 3.1.4 Influence of crystal habit on dissolution It has been shown that an in-depth understanding of the crystallisation process can be applied to confer habit modification in crystalline materials. It is also known through studies of crystallization and comminution that exposure of different crystal faces determines the nature of those faces45, which in turn will influence the wettability and subsequent dissolution of an Active drug substance. A number of examples in the literature demonstrate the effects of changing crystal morphology on in vitro dissolution rate, with potential for improving bioavailability. The habit modification of dipyridamole by crystallization using different solvents, additives and crystallisation conditions has been reported46. The dissolution rate of rod shaped particles crystallized from benzene was notably more rapid than for rectangular needle shaped crystals produced using methanol. In studies of phenytoin, the morphology of crystals produced under similar conditions following recrystallisation from ethanol and acetone was shown to be needle-like and rhombic respectively47. This change in habit was ascribed to stronger interaction of acetone with the hydroxyl groups of phenytoin, due to its relatively high polarizability. Although there were some differences in dissolution rate observed between crystalline powders of different morphology, these differences were predominantly attributed to

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REVIEW LITERATURE changes in surface area rather than improvements in the wetting of more polar surface moieties. However, when correcting for the contribution of surface area48, have suggested that the crystal habit of doped crystals had a notable role to play in the enhancement of intrinsic dissolution rate of phenytoin due to an increased abundance of polar groups. Although showing potential as a crystal engineering approach to dissolution rate enhancement, there are only a limited number of examples reported where the approach of habit modification has resulted in notable enhancement of systemic exposure in human subjects or in suitable animal models. These increases in dissolution appear to be derived from a combination of changes to crystal habit, size and even polymorphic form. Further exploration of this field is therefore required to fully establish this approach as an effective means of intentionally augmenting the bioavailability of poorly soluble drugs.

3.1.5 Crystal growth and polymorph The impact of crystal form on pharmaceutical development has been the subject of numerous reviews with Singhal and Curatolo providing one of the most recent articles in 200449. In particular, the influence of crystalline modification on drug dissolution and bioavailability has been considered for a whole library of molecules and was first highlighted for the well known example of chloramphenicol palmitate in the late 1960s, in which metastable polymorph B was shown to provide notably greater absorption in humans than polymorph A50. It was suggested that

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REVIEW LITERATURE where large free energy differences between polymorphs exist, the greater solubility of the metastable form could be exploited to enhance absorption and bioavailability.

3.1.6 The influence of crystal form on drug solubility Dissolution and bioavailability Although the utilization of metastable polymorphs offers a route to improved dissolution and oral bioavailability, concerns still exist with respect to conversion of these materials to more stable crystalline forms during processing and storage. Nonetheless, there have been numerous reports demonstrating the influence of polymorphic and crystalline form on dissolution rate and/or oral bioavailability. These have included discussions on the
53

crystalline

forms

of

phenobarbital51,

spironolactone52 and carbamazepine

in which metastable crystalline forms have

provided enhanced dissolution behaviour. Pandit et al.54 also showed differences in dissolution rate, area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax) fortwo different polymorphs of phenylbutazone in beagle dogs, whilst Singhal and Curatolo reviewed a number of examples showing differences in pharmacokinetic profiles in human subjects relating to batch to batch variations in the polymorphic forms of carbamazepine and oxytetracycline55.

3.1.7 Micromeritic properties of pharmaceutical powders influencing tableting The formulation and manufacture of solid oral dosage forms and tablets, in particular, has undergone rapid change and development over the last several decades with the emergence of pre-compression, high-speed processes automated weight control system and the availability of many new direct compression materials. 16

REVIEW LITERATURE The advent of these sophisticated techniques has resulted in considerable reduction in material handling and time. One of the most revolutionary technologies amongst these is that of direct compression. The process offers the distinct advantages of economy, processing without the need for moisture and heat and optimization of tablet disintegration. Generally, the tablets comprise of mixture of the active ingredient, vehicle, lubricant, and disintegrating agent etc, therefore, it is important to elucidate the compaction performances of these tablet mixtures such as its compressibility and the force of compaction. Especially in the direct tableting method, it is necessary to increase the flowability and compressibility of the bulk drug powder in order to ensure a steady supply of powder mixtures to the tableting machine and sufficient mechanical strength of the compacted tablet. In addition to the efforts to increase the efficiency of the manufacturing process, it is also important to increase the bioavailability of the drug by improving the solubility of the bulk drug powder. That is, it has become necessary to increase the added value by endowing the drug particle itself with high functionality. Fine crystals are preferred over large crystals of poorly soluble drug substances as they provide greater bioavailability. However, Microcrystallization of crystals can change the Micromeritic properties such as compressibility, packability and flowability and thus prevent efficient powder processing. To prevent this problem, the micronized drug is converted into different crystals by crystallization technique. It could be more efficient to transform the micronized drug itself into a crystals form during the crystallization process as the last of synthesis. 17

REVIEW LITERATURE 3.2 Mechanism of crystal growth The interface between a crystal and its vapor can be molecularly sharp at temperatures well below the melting point. An ideal crystalline surface grows by the spreading of single layers, or equivalently, by the lateral advance of the growth steps bounding the layers. For perceptible growth rates, this mechanism requires a finite driving force (or degree of supercooling) in order to lower the nucleation barrier sufficiently for nucleation to occur by means of thermal fluctuations. In the theory of crystal growth from the melt, Burton and Cabrera have distinguished between two major mechanisms: Non-uniform lateral growth. The surface advances by the lateral motion of steps which are one interplanar spacing in height (or some integral multiple thereof). An element of surface undergoes no change and does not advance normal to itself except during the passage of a step, and then it advances by the step height. It is useful to consider the step as the transition between two adjacent regions of a surface which are parallel to each other and thus identical in configuration displaced from each other by an integral number of lattice planes. Note here the distinct possibility of a step in a diffuse surface, even though the step height would be much smaller than the thickness of the diffuse surface. Uniform normal growth. The surface advances normal to itself without the necessity of a stepwise growth mechanism. This means that in the presence of a sufficient thermodynamic driving force, every element of surface is capable of a continuous change contributing to the advancement of the interface. For a sharp or discontinuous surface, this continuous change may be more or less 18

REVIEW LITERATURE uniform over large areas each successive new layer. For a more diffuse surface, a continuous growth mechanism may require change over several successive layers simultaneously.

3.3 Factors Affecting Crystallization 1. Solvent moderate solubility is best. Super saturation leads to sudden precipitation and smaller crystal size

Solvent Considerations Moderate solubility is best (avoid supersaturation) Like dissolves like Hydrogen bonding can help or hinder crystallization. Presence of benzene can help crystal growth Avoid highly volatile solvents Avoid long chain alkyl solvents can be significantly disordered in crystals. Choose solvents with rigid geometries 2. Nucleation fewer nucleation sites are better. Too many nucleation sites (i.e. dust, hairs, etc.) lower the average crystal size. Nucleation & Growth Crystals initially form via nucleating events Excess nucleation sites cause smaller average crystal size Ambient dust, filter paper fibers, hair, broken off pipette tips all provide

opportunities for nucleation take steps to remove them. 3. Mechanics mechanical disturbances are bad.

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REVIEW LITERATURE Crystals grow by the ordered deposition of the solute molecules onto the surface

of a pre-existing crystal. Crystal growth is facilitated by the environment changing slowly over time. Keep crystal growth vessel away from sources of mechanical agitation (e.g. vibrations) 4. Time faster crystallization is not as good as slow crystallization. Faster crystallization higher chance of lower quality crystals Quality crystals grow best over time in near equilibrium conditions The longer the time, the better the crystals

Crystal Growing Techniques

5. Slow Evaporation: simplest to set up. Has a drawback: solute can oil out, crystals stick to sides of vessel making them difficult to extract from vessel without breaking them. 6. Slow Cooling: Soluble when hot, insoluble when cool. o Use Dewar to slow the cooling process. o Use a Oil Bath, and cut the heat to the bath for slow cooling. o Use a thermally insulated environment. 7. Variations: use binary or tertiary solvent mixtures. Use solvent with similar boiling points and other properties.

3.4 Various methods to increase solubility There are different methods used to improve absorption of poorly soluble drugs and then enhancement in bioavailability Table 1.

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REVIEW LITERATURE

Physical Modification Modification Of Crystal Habitat Solubilization By Sufactant Particle Size Reduction Complexation Drug Dispersion In Carrier

Chemical Modification Salt Formation Prodrug

Other Method Hydrotophy Nanosuspension Supercritical Fluid Process Micellar Solubilization Spray Drying Freeze Drying Spherical Crystallization

3.4.1 Physical Modification Modification of crystal habitat The crystal habit of a drug is an important variable in pharmaceutical manufacturing. Different crystal forms of a particular drug possess different planes and thus differ not only in their specific surface, but also in their free surface energy. Therefore, they may exhibit different physicomechanical properties56, 57. Different crystalline forms of drugs, as well as amorphous forms, have different physical properties that may affect both stability and bioavailability. Solubilization by surfactant The use of media containing surfactants is the most popular method because of its simulation with various surfactants present in the gastrointestinal fluid, e.g., bile salts, lecithin, cholesterol and its esters. Surfactant monomers above their cmc, aggregate to form colloidal moieties known as micelles which are capable of encapsulating the drug molecules resulting in reduction in the interfacial tension and improved solubility of the drug in the medium58. 21

REVIEW LITERATURE Particle size reduction The solubility of drug is often intrinsically related to drug particle size; as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows greater interaction with the solvent which causes an increase in solubility. Complexation There are numerous approaches available and reported in literature to enhance the solubility of poorly water soluble drug. The techniques are chosen on the basis of certain aspects such as properties of drug under consideration, nature of excipients to be selected and nature of intended dosage form. Among these approaches salt formation, solubilization, particle size reduction, solid dispersion, and solvent deposition technique are most frequently used. But, there are practical limitations of these techniques59. 3.4.2 Chemical modification For organic solutes that are ionizable, changing the pH of the system may be simplest and most effective means of increasing aqueous solubility. Under the proper conditions, the solubility of an ionizable drug can increase exponentially by adjusting the pH of the solution. A drug that can be efficiently solubilized by pH control should be either weak acid with a low pKa or a weak base with a high pKa the use of salt forms is a well known technique to enhanced dissolution profiles. Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. An alkaloid base is, generally, slightly soluble in water, but if the pH of medium is reduced by addition of acid, and the solubility of the base is increased as the pH continues to be reduced. The reason for this increase in solubility is that the base is converted to a salt, which is relatively soluble in water. The 22

REVIEW LITERATURE solubility of slightly soluble acid increased as the pH is increased by addition of alkali, the reason being that a salt is formed60. 3.4.3 Other method Hydrotrophy Hydrotrophy is a solubilisation process, whereby addition of a large amount of second solute, the hydrotropic agent results in an increase in the aqueous solubility of first solute. Hydrotropic agents are ionic organic salts, consists of alkali metal salts of various organic acids. Additives or salts that increase solubility in given solvent are said to salt in the solute and those salts that decrease solubility salt out the solute. Several salts with large anions or cations that are themselves very soluble in water result in salting in of non electrolytes called hydrotropic salts; a phenomenon known as hydrotropism. Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives. The mechanism by which it improves solubility is more closely related to complexation involving a weak interaction between the hydrotropic agents like sodium benzoate, sodium acetate, sodium alginate, urea, and the poorly soluble drugs61, 62. Nanosuspension

Nanosuspension technology has been developed as a promising candidate for efficient delivery of hydrophobic drugs. This technology is applied to poorly soluble drugs that are insoluble in both water and oils. A pharmaceutical nanosuspension is a biphasic system consisting of nano sized drug particles stabilized by surfactants for either oral and topical use or parenteral and pulmonary administration. The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600nm62, 63. 23

REVIEW LITERATURE Supercritical fluid processes Another novel nanosizing and solubilisation technology whose application has increased in recent years is particle size reduction via supercritical fluid (SCF) processes. Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both a liquid and a gas. At near-critical temperatures, SCFs, are highly compressible allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of the fluid that largely determine its solvent power. Once the drug particles are solubilised within the SCF (usually carbon dioxide), theymay be recrystallised at greatly reduced particle sizes. The flexibility and precision offered by SCF processes allows micronisation of drug particles within narrow ranges of particle size, often to submicron levels. Current SCF processes have demonstrated the ability to create nanoparticulate suspensions of particles 52,000nm in diameter. Several pharmaceutical companies, such as Nektar Therapeutics and Lavipharm, are specializing in particle engineering via SCF technologies for particle size reduction and solubility enhancement64, 65. Micellar Solubilization

The use of surfactants to improve the dissolution performance of poorly soluble drug products is probably the basic, primary, and the oldest method. Surfactants reduce surface tension and improve the dissolution of lipophilic drugs in aqueous medium. They are also used to stabilise drug suspensions. When the concentration of surfactants exceeds their critical micelle concentration (CMC, which is in the range of 0.050.10% formost surfactants), micelle formation occurs which entrap the drugs within the micelles. This is known as micellization and generally results in enhanced 24

REVIEW LITERATURE solubility of poorly soluble drugs. Surfactant also improves wetting of solids and increases the rate of disintegration of solid into finer particles66. Commonly used nonionic surfactants include polysorbates, polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols. Surfactants are also often used to stabilize microemulsions and suspensions into which drugs are dissolved67, 68. Spray drying Spray-drying is a common technique used in pharmaceuticals to produce a dry powder from a liquid phase. A spray dryer is a device used in spray drying. It takes a liquid stream and separates the solute or suspension as a solid and the solvent into a vapour. The solid is usually collected in a drum or cyclone. The liquid input stream is sprayed through a nozzle into a hot vapour stream and vaporised. Solids form as moisture quickly leaves the droplets. A nozzle is usually used to make the droplets as small as possible, maximizing heat transfer and the rate of water vaporization. Droplet sizes can range from 20 to 180 m depending on the nozzle. Spray drying consists of the following unit operations: Pre-concentration of liquid, Atomization (creation of droplets), Drying in stream of hot, dry air, Separation of powder from moist air cooling69. Freeze drying

It is also known as lyophilisation technique. In order to get a porous, amorphous powder with high degree of interaction between drug and CD, lyophilization/freeze drying technique is considered suitable. In this technique, the solvent system from the solution is eliminated through a primary freezing and subsequent drying of the solution containing both drug and CD at reduced pressure. Thermolabile substances 25

REVIEW LITERATURE can be successfully made into complex form by this method. Lyophilization/freeze drying technique is considered as an alternative to solvent evaporation and involves molecular mixing of drug and carrier in a common solvent70. Spherical crystallization The technique of spherical crystallization can transform crystals directly into a compacted spherical form which is found to have good flowability, compressibility, packability and also good solubility. Thus, spherical crystallization can be defined as a modified crystallization technique by which it is possible to produce directly compressible drugs without the use of excipients70. Recrystallization Recrystallization is the primary method for purifying solid organic compounds. Compounds obtained from natural sources or from reaction mixtures almost always contain impurities. The impurities may include some combination of insoluble, soluble, and colored impurities. To obtain a pure compound these impurities must be removed. Each is removed in a separate step in the recrystallization procedure. The six steps used to recrystallize a compound are 1. Carry out solubility tests to determine a suitable solvent 2. Dissolve the solute in a minimum of near-boiling solvent 3. Allow the solution to cool slowly and undisturbed to room temperature (RT) then possibly to ice temperature 4. Collect the crystals by filtration 5. Rinse the crystals with a minimum amount of ice-cold solvent and 6. Allow the crystals to dry.
<

3.5 The crystallization method chosen for the present study are: 26

REVIEW LITERATURE 1. Spherical crystallization 2. Crystallization by Spray drying technique 3. Crystallization by Freeze drying technique 4. Super cooling crystallization technique 5. Recrystallization technique 3.5.1 Spherical crystallization The technique of spherical crystallization can transform crystals directly into a compacted spherical form which is found to have good flowability, compressibility, packability and also good solubility. Thus, spherical crystallization can be defined as a modified crystallization technique by which it is possible to produce directly compressible drugs without the use of excipients71. The nature of the solid drug substances plays important role in design of the formulation of insoluble drugs and processing of crystalline powders. The effectiveness of the solid dosage forms in releasing its drug for systemic absorption depends on dissolution rate of the solid drugs. Frequently, dissolution is the ratelimiting step in bio-absorption for the drugs of low aqueous solubility. Several techniques are employed to enhance the dissolution of the drugs that are poorly soluble in water. Spherical crystallization has been described as a very effective technique in improving the dissolution behavior of some of the drugs that are characterized by low water solubility and low dissolution profiles. Spherical agglomeration process was developed in the early 1960s at the National Research Council of Canada72 as a general process for selective separation of one kind of particulate from a liquid suspension containing several different solids. One of

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REVIEW LITERATURE the prominent features of the spherical agglomeration process is its versatility in controlling the type and size of the product7. 3.5.1.1 Theoretical background and Techniques: The principle of agglomeration was initially applied to coal and minerals. Owing to the naturally hydrophobic properties of coals, they agglomerate with ease and separate from the ash constituents by applying virtually any mode of agitation in the presence of sufficient hydrocarbons as bridging liquids. But the process could not achieve commercialization due to high cost of the bridging oils. Since 1980 spherical crystallization has been studied as a size enlargement operation in the field of pharmacy. 3.5.1.2 Theory: Finely divided solids in liquid suspension can be agglomerated and separated from the suspending liquid by the addition of a small amount of bridging liquid, which preferentially wets the surface of the solid. Thus surface properties of the crystals and nature of the bridging liquid play an important role in the agglomeration process. Smith and Puddington73 studied the mechanical agglomeration of Barium sulphate in benzene and inferred that hydrophilic surface, is preferentially wetted and agglomerated by using bridging liquid of polar nature like water. 3.5.1.3 Process principles: Preferential wetting of lipophilic /hydrophobic particles by bridging liquid forms the fundamental basis for the separation of particulate material from aqueous suspension by agglomeration74, 75, 76. In the presence of adequate amount of bridging liquid and sufficient mechanical agitation the particle coated with bridging liquid collide with each other and form into agglomerate due to the interfacial tension of the bridging 28

REVIEW LITERATURE liquid and capillary attraction of liquid bridges between the particles. The behavior of suspension of fine particles that are formed during crystallization process, to which small amount of bridging liquid is added is controlled by three main factors, in order of importance; Free energy relationships at the liquid-liquid-solid interface The amount of second liquid (Bridging liquid) used in relation to the amount of solids and The type and intensity of mixing employed. 3.5.1.4 Thermodynamics: From a thermodynamic standpoint, the driving force for the wetting by the bridging liquid and subsequent agglomeration of hydrophobic/lipophilic particle is the reduction in the total surface free energy of the system77. 3.5.1.5 Mechanism of crystal growth Bemer et. a178 further proposed four regions in growth of agglomerates in simple Spherical crystallization method, as follows: i. Flocculation Zone: Where pendular bridges form loose open flocs of particles. ii. Zero Growth zone - Loose flocs get transformed into tightly packed pallets during which the entrapped suspension fluid is squeezed out followed by squeezing of bridging liquid onto the surface of small flocs causing pore space in the pellet to be completely filled with the bridging liquid. The driving force for this transformation is provided by the agitation of the slurry causing liquid turbulence, pellet - pellet and pellet - stirrer collision.

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REVIEW LITERATURE iii. Fast - Growth Zone: The fast growth of the agglomerate takes place when sufficient bridging liquid has squeezed out to the surface of small agglomerates. iv. Constant - Size Zone: In this zone the agglomerates cease to grow, or even show slight reduction in size. Here the frequency of coalescence is balanced by the breakage frequency of agglomerates. 3.5.1.6 Kinetics: Capes and Kawashima79 described the spherical crystallization kinetics in terms of the rate of decrease in the residual concentration of drug in crystallization solvent. It was found that the rate of decrease in residual concentration was a function of agitation speed of the system and of the concentration difference between the initial and the equilibrium state. They concluded that spherical agglomeration is a first order process whereas Vanangamudi and Tadimeti Rao80 proposed it to be second order kinetics with two constants describing the growth kinetics. 3.5.1.7 Operating variable The operating variables include Agitator speed Drug concentration pH and temperature of the system Type and amount of the bridging liquid Type, amount and method of dispersion. 3.5.1.8 Factors controlling the Process of spherical crystallization 1. Solubility profile

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REVIEW LITERATURE Venkadari Rammohan Gupta81 described the selection of solvent is dictated by the solubility characteristic of the drug. Solvent system for spherical crystallization consisting of a poor solvent (suspending liquid), a good solvent for a drug and bridging liquid. Physical form of the product i.e., whether micro-agglomerates or irregular macro-agglomerates or a paste of the drug substance can be controlled by the selection of proper solvent proportions. The proportion of the solvents to be used is determined by carrying out solubility studies and constructing triangular phase diagram to define the region of mutual immiscibility. Ternary diagrams The drug substance in solvent, bridging liquid and medium yields a phase diagram with distinct zones or regions. In the example shown in Figure1, the monophasic drug substance/acetone/ water liquid region is in equilibrium with different phases as a function of the mass ratio of acetone in the water/acetone mixture82.

Figure 1: Model of ternary diagram In region A drug is highly soluble in acetone; in region B drug substance is even more soluble. Solubility of drug substance decreases markedly in the region C. Regions between A and C, the monophasic region is in equilibrium with biphasic 31

REVIEW LITERATURE liquid/solid region (crystallization of drug substance). A liquid with a high drug concentration which is non miscible in a liquid with a low drug concentration appears and forms an emulsion. In the region D, the aqueous medium limits the solubility of the drug substance so the liquid/liquid region disappears, yielding equilibrium between regions D and E (crystallization of drug substance). In the region above the phase separation curve the system is completely miscible, but in the region just below the separation curve will provide small quantity of bridging liquid. 2. Mode and intensity of agitation High-speed agitation is necessary to disperse the bridging liquid throughout the system. The product of a high-speed shaker blender is usually in the form of irregular agglomerates. When tank is used as the reaction vessel, more irregular, but less spherical agglomerates could be prepared. An inclined pan and drum agglomerator facilitates the size enlargement process. Any change in agitation pattern or fluid flow would be reflected as a change in force acting on agglomerate, which ultimately affects the shape of agglomerate. Mechanical agitation is the prime variable affecting the process and is necessary to bring the particles into proximity so that the force responsible for agglomeration may become operative. The extent of mechanical agitation in conjunction with the amount of bridging liquid determines the rate of formation agglomerates and their final size. High shear quickly forms agglomerates and reworks them by redispersion and reformation allowing cleaner particle to form, however, high shear limits the size of the agglomerates to small diameter. 3. Temperature of the system

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REVIEW LITERATURE Espitalier et al.,49 have studied the spherical crystallization, modeling of the emulsion solvent diffusion technique. Study revealed that the temperature difference between the drug solution and crystallizing medium has a significant influence on the shape, size and texture of the spherical agglomerates. Large difference in the temperatures of crystallizing liquid and non-solvent (>350 C) produce small spherical crystals with thick outer crust and no preferential orientation of crystals. The core is hollow. These grains remain soft for long time, indicating that a high residence time in the crystallizer is required before filtration. If the temperature difference is small (10-350 C), grains remains spherical, may have hallow core, but are made up of two layers. The outer crust is less dense and surface is covered with crystals. The internal layer is very porous and the crystals are oriented towards center. If the temperature difference is less than 100 C the outer crust is more porous. The effect of temperature on spherical agglomeration is probably due to the effect of temperature on the solubility of the drug substance in ternary system. The average size of agglomerates was the smallest at the crystallization temperature 100 C, at temperature higher or lower than 100 C, the size and variation increased. At higher temperature, the larger agglomerates were produced initially and the equilibrium state attained more rapidly than at lower temperature. At low temperature, it was characteristic that the growth rate of crystal was slow at the initial stage but became faster at a later stage. At low temperature, the initial numbers of crystals produced were greater than at high temperature, the number of nuclei increased with decreased crystallization temperature. 4. Residence time

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REVIEW LITERATURE The time for which agglomerates remain suspended in reaction mixture affects their strength. 5. Methods of Spherical crystallization Spherical crystallization is a solvent exchange crystallization method in which crystal agglomeration is purposely induced through the addition of a third solvent, termed the "bridging liquid"82. Crystal agglomeration, which is usually avoided during normal processing, is performed in a controlled fashion during spherical crystallization to bring about improved flow and compaction properties to the material. These properties are highly advantageous for pharmaceutical production. Currently, optimization of spherical crystallization is difficult as the mechanism and effect of process parameters are unclear. In-process monitoring of the chord length distribution (CLD) to track the rate and degree of change to particle dimension and particle count can provide insight into the dynamics of spherical crystallization. The main requirement in the spherical crystallization system is that, it should provide a small amount of bridging liquid. Following are the methods to prepare spherical crystals. Spherical agglomeration method (SA) Quasi-Emulsion solvent diffusion method (QESD) Ammonia diffusion method Neutralization method 3.5.2 Simple Spherical Crystallization Method This process involves formation of fine crystals and their agglomeration. Crystallization is generally achieved by change of solvent or salting out. The solution of the material in a "good solvent" is poured in a "poor solvent" under controlled conditions, so as to favour formation of fine crystals. Agitating the crystals in a liquid 34

REVIEW LITERATURE suspension and adding a bridging liquid which preferentially wets the crystal surface to cause binding forms the agglomerates. The agglomerate may be spherical, if the amount of this bridging liquid and the rate of agitation are controlled.

Figure 2: Simple spherical crystallization. Kawashima et al., (83) carried out crystallization of salicylic acid by change of solvent, ethanol as good solvent and water as a poor solvent. The crystals were agglomerated using chloroform as a bridging liquid. In solvent change method when bridging liquid was poured into IPA- water mixture, small amount of chloroform was liberated from the system. These precipitated microcrystals may initially form loose agglomerates held together by discrete bridges of chloroform.

Figure 3: Mechanism of spherical agglomeration. These loose agglomerates in funicular state could coalesce with small particles and individual crystals. However, they would not be able to coalesce with other large agglomerates because they have no excess bridging liquid on the surface. On further agitation, the filling ratio of chloroform in agglomerates would increase under the

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REVIEW LITERATURE shear force, and finally agglomerates reach capillary state. These agglomerates could coalesce into larger agglomerates with a slight increase in the apparent density. kawashima yoshiaki al.,84 have studied that Sodium theophylline was crystallized by salting out from the solution of theophylline in aqueous ethylenediamine solution by addition of equal volume of (15% w/v) sodium chloride solution. The agglomerate crystals were produced by addition of adequate amount of ethanol and chloroform. 3.5.3 Quasi - Emulsion Solvent Diffusion Method By this method, spherical crystallization can be carried out using a mixed system of two or three partially miscible solvents, i.e. bridging liquid - poor solvent system or good solvent - bridging liquid - poor solvent system. When bridging liquid (or plus good solvent) solution of the drug was poured into poor solvent (dispersing medium) under agitation, quasi emulsion droplets of bridging liquid or good solvent from the emulsion droplet into the dispersing medium induce the crystallization of the drug, followed by agglomeration85.

Figure 4: Emulsion solvent diffusion method

3.5.4 Ammonia Diffusion System, Method (A D S' method) Puechagut et al.,54 developed a novel method for spherical crystallization of norfloxacin. 36

REVIEW LITERATURE

Figure 5: Ammonia diffusion method Puechagut H.G. et al prepared norfloxacin agglomerated crystals by a spherical crystallization technique using the ammonia diffusion system. The technique makes it possible to agglomerate amphoteric drug norfloxacin, which cannot be agglomerated by conventional procedures. When ammonia water solution of norfloxacin poured into an acetone, dichloromethane mixture under agitation, a small amount of ammonia was liberated in the system. The ammonia water solution played a role both as a good solvent for the drug and as a bridging liquid, allowing the crystal collection to take place in one step. 3.5.5 Neutralization method This process involves the formation of fine crystals and their agglomeration; the crystallization is generally achieved by neutralization method.

Figure 6: Neutralization method The drug was dissolved in a sodium hydroxide solution and hydroxy propyl ethyl cellulose aqueous solution and hydrochloric acid was added to neutralize the sodium 37

REVIEW LITERATURE hydroxide solution of tolbutamide and crystallize out. The bridging liquid was added drop wise followed by agglomeration of the tolbutamide crystals. 3.5.6 Applications The spherical crystallization technique can enable subsequent processes such as Separation, filtration, drying etc., more efficiently. It highly affects the secondary properties of the crystals such as flowability, compressibility, and wettability of the materials. 3.5.2 Crystallization by Spray drying technique: 3.5.2.1 Concept of spray drying technique The production of particles from the process of spraying has gained much attention in recent years. These efforts have resulted in spray technology being applied to the manufacture of particles to generate products ranging from pharmaceutical direct compression excipients and / or granulations to microencapsulated flavors. The two main spray techniques are spray drying & spray congealing. The action in spray drying is primarily that of evaporation, whereas in spray congealing it is that of a phase change from a liquid to a solid. The two processes are similar, except for energy flow. In the case of spray drying, energy is applied to the droplet, forcing evaporation of the medium resulting in both energy and mass transfer through the droplet. In spray congealing, energy only is removed from the droplet, forcing the melted to solidify86. Spray drying is the most widely used industrial process involving particle formation and drying. It is highly suited for the continuous production of dry solids in either powder, granulate or agglomerate form from liquid feedstocks as solutions, emulsions and pumpable suspensions. Therefore, spray drying is an ideal process where the end38

REVIEW LITERATURE product must comply with precise quality standards regarding particle size distribution, residual moisture content, bulk density, and particle shape. 3.5.2.2 Principle of spray drying: There are three fundamental steps (figure 7) involved in spray drying87. 1) Atomization of a liquid feed into fine droplets. 2) Mixing of these spray droplets with a heated gas stream, allowing the liquid to evaporate and leave dried solids. 3) Dried powder is separated from the gas stream and collected.

Figure - 7 Main process stages involved in spray drying process Spray drying involves the atomization of a liquid feedstock into a spray of droplets and contacting the droplets with hot air in a drying chamber. The sprays are produces by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions. Powder is discharged continuously from the drying chamber. Operating conditions and dryer design are selected according to the drying characteristics of the product and powder specification. 39

REVIEW LITERATURE 1. Atomization The atomizing device, which forms the spray, is the heart of the spray drying process. Atomizer: Equipment that breaks bulk liquid into small droplets, forming a spray. Prime functions of atomization are88, 89: a. A high surface to mass ratio resulting in high evaporation rates, b. Production of particles of the desired shape, size and density. The aim of atomizing the concentrate is to provide a very large surface, from which the evaporation can take place. The smaller droplets, the bigger surface, the easier evaporation, and a better thermal efficiency of the dryer are obtained. The ideal from a drying point of view would be a spray of drops of same size, which would mean that the drying time for all particles would be the same for obtaining equal moisture content. Over the years several researches have studied the mechanism by which atomization takes place and several theories have evolved. The most widely accepted are based on the liquid jet theory described in 1878 by Lord Rayleigh. A liquid stream accelerated by the force of gravity is pulled apart or disintegrated into teardrop-shaped droplets. The surface tension of the liquid causes the droplet, suspended in air, to form itself into a sphere. In order to produce top-quality products in the most economical manner, it is crucial to select the right atomizer. Three basic types of atomizers are used commercially: A. Rotary atomizer (atomization by centrifugal energy) B. Pressure nozzle (atomization by pressure energy) C. Two-fluid nozzle (atomization by kinetic energy) 40

REVIEW LITERATURE Ultrasonic energy & vibrations have also been studied, but as yet have found few commercial applications. The selection of a specific atomizer is made based on the properties of the feed, the desired powder properties, the dryer type and its capacity and the atomizer capacity. A. Rotary atomizers: Atomization by centrifugal energy Rotary atomizer (Figure 8) uses the energy of a high speed-rotating wheel to divide bulk liquid into droplets. Feedstock is introduced at the center of the wheel, flows over the surface to the periphery and disintegrates into droplets when it leaves the wheel.

Figure- 8 Rotary atomizer Advantages of rotary atomizers: -Great flexibility & ease of operation. -Low pressure feed system. -No blockage problems. -Handling of abrasive feeds. -Ease of droplet size control through wheel speed adjustment. Disadvantages of rotary atomizers: -Produce large quantities of fine particles, which can result in pollution control problems. 41

REVIEW LITERATURE -High capital cost. -Very expensive to maintain. -Cannot be used in horizontal dryers. -Difficult to use with highly viscous materials. Because of the problems and costs associated with rotary atomizers, there is interest within segments of the spray dry industry in replacing rotary atomizers with spray nozzles. B. Pressure nozzles: Atomization by pressure energy Pressure nozzl42, 48 (Figure 9) is the most commonly used atomizer for spray drying. Nozzles generally produce coarse, free flowing powders than rotary atomizers. Pressure nozzles used in spray drying are called vortex nozzles because they contain features that cause the liquid passing through them to rotate. The rotating fluid allows the nozzle to convert the potential energy of liquid under pressure into kinetic energy at the orifice by forming a thin, high-speed film at the exit of the nozzle. As the unstable film leaves the nozzle, it disintegrates, forming first ligaments and then droplets. Pressure nozzles can be used over a large range of flow rates, and can be combined in multiple-nozzle installations to give them a great amount of flow rate and particle size flexibility. The range of operating pressure range for pressure nozzles used in spray drying is from about 250 PSI (17.4 bar) to about 10,000 PSI (690 bar).

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REVIEW LITERATURE

Figure-9 Pressure nozzle C. Two-fluid or Pneumatic nozzles: Atomization by kinetic energy Liquid feedstock and compressed air (or steam) is combined in a two-fluid nozzle (Figure 10). The design utilizes the energy of compressed gas to atomize the liquid. Two advantages of the two-fluid nozzle are its ability to produce very fine particles and to atomize highly viscous feeds. However, two-fluid nozzles are expensive to operate because of the high cost of compressed air. Two fluid nozzles are often used in laboratory and pilot plant spray dry applications because of their ability to produce a wide range of flow rates and droplet sizes. The range of operating pressure range for pressure nozzles used in spray drying is from about 250 PSI (17.4 bar) to about 10,000 PSI (690 bar).

Figure- 10 two fluid nozzle Ultrasonic Atomization Recently ultrasonic56 energy has been used in place of pressure or centrifugal force to form droplets. In this method, a liquid is placed on a rapidly vibrating surface at 43

REVIEW LITERATURE ultrasonic frequencies. At sufficiently high amplitude, the liquid spreads, becomes unstable and collapses, resulting in the formation of very fine droplets. These devices are excellent for droplets below 50 microns. Their use is expected to grow over the next few years.

Parameters to be controlled The pharmaceutical spray-dried products have important properties55, 56 like -Uniform Particle size, -Nearly spherical regular particle shape, -Excellent Flowability, -Improved Compressibility, -Low Bulk Density, -Better Solubility, -Reduced Moisture Content, -Increased Thermal stability, and suitability for further applications. Such product characteristics majorly depend on the physical properties of feed, equipment components and processing parameters by modifying the spray drying process, it is possible to alter and control the mentioned properties of spray-dried powders. It is certainly very useful for the development of drug delivery systems. With the latest developments on spray drying technologies and with the increasing demand for highly defined particles properties in the pharmaceutical industry, there have been developed a range of spray drying units able to operate under the most stringent cGMP conditions. 44

REVIEW LITERATURE All spray dryers units operate with nitrogen as the drying gas and are fit to handle both aqueous and organic feeds (solutions, emulsions and pumpable suspensions). Advantages and disadvantages In the world of industrial dryers, there are few types that accept pumpable fluids as the feed material at the inlet end of the process and produce dry particulate at the outlet. The main advantage of spray drying is the remarkable versatility of the technology, evident when analyzing the multiple applications and the wide range of products that can be obtained. From very fine particles (Figure-11) for pulmonary delivery to big agglomerated powders for oral dosages, from amorphous to crystalline products and the potential for one-step formulations, spray drying offers multiple opportunities that no other single drying technology can claim. This flexibility and reproducibility makes spray drying the process of choice for many industrial drying operations.

Figure- 11 Formation of product in spray drying

Advantages of spray drying 1 Able to operate in applications that range from aseptic pharmaceutical processing to ceramic powder production. 45

REVIEW LITERATURE 2 It can be designed to virtually any capacity required. (Feed rates range from a few pounds per hour to over 100 tons per hour). 3 The actual spray drying process is very rapid, with the major portion of evaporation taking place in less than a few seconds. 4 Adaptable to fully automated control system that allows continuous monitoring and recording of very large number of process variables simultaneously. 5 Wide ranges of spray dryer designs are available to meet various product specifications. 6 It has few moving parts and careful selection of various components can result in a system having no moving parts in direct contact with the product, thereby reducing corrosion problems. 7 8 It can be used with both heat-resistant and heat sensitive products. As long as they are can be pumped, the feedstock can be in solution, slurry, paste, gel, suspension or melt form. 9 Offers high precision control over Particle size, Bulk density, Degree of crystallinity, organic volatile impurities and residual solvents. 10 Powder quality remains constant during the entire run of the dryer. Nearly spherical particles can be produced, uniform in size and frequently hollow, thus reducing the bulk density of the product.

Disadvantages of spray drying 1. The equipment is very bulky and with the ancillary equipment is expensive.

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REVIEW LITERATURE 2. The overall thermal efficiency is low, as the large volumes of heated air pass through the chamber without contacting a particle, thus not contributing directly to the drying. Applications Degree of application decides the importance of process. Spray drying technology is widely applied. In pharmaceutical fields as well as non-pharmaceutical fields. Non-pharmaceutical applications Chemical industry, Ceramic materials, Detergents, soaps and surface-active agents, Pesticides, herbicides, fungicides and insecticides, Dyestuffs, pigments, fertilizers, mineral floatation concentrates, inorganic chemicals, organic chemicals, spray concentration (purification), milk products, egg products, food and plant products, fruits, vegetables, carbohydrates and similar products, slaughterhouse products, fish products and many others. Pharmaceutical applications Many pharmaceutical and biochemical products are spray dried, including antibiotics, enzymes, vitamins, yeasts, vaccines, and plasma. The spray drying capacity required for these products ranges from high, in the case of yeasts to low, as in the case of plasma. Spray drying of most pharmaceutical and biochemical products is done using two-fluid or pressure nozzle atomizers. Pharmaceutical products Like Algae, antibiotics and moulds, bacitracin, penicillin, streptomycin,

sulphathiazole, tetracycline, dextran, enzymes, hormones, lysine (amino acids), pharmaceutical gums, sera, spores, tableting constituents, vaccines, vitamins, yeast products, tannin products, etc. 47

REVIEW LITERATURE Granulation and tabletting: When compared with other granulation methods, spray drying stands out as unique in several ways. Because the feed to a spray dryer is a homogenous liquid, it eliminates the concern over blending of dry components with liquids. Although it is the application of shear forces in the centrifugal atomizer that creates a spray, this form of energy generally will not destroy microencapsulated material as can happen in high shear granulators. Spray drying technique has been used for granulating, for slow-release granulations of magnesium carbonate, theophylline and acetaminophen88. The spherical composite particles consisting of amorphous lactose and sodium alginate were prepared by spray drying their aqueous solutions using rotary atomizing spray-dryer. The SD composite particles had good compactibility and excellent micrometric properties as filler for direct tableting of controlled release matrix tablets
89

By spray-drying Amioca starch and Carbopol 974P mixtures a range of potential bioadhesive carriers was obtained with excellent bioadhesive properties. Solid dispersions of theophylline with chitosan as a carrier were prepared using a spraydrying method90, 91 Modified extended release matrix tablet were produced by compressing material made by spray-drying Theophylline slurried in an aqueous ammoniated solution of cellulose enteric polymers such as cellulose acetate phthalate. Both enteric release and sustained release can be achieved. Spray drying allowed the rapid formation of theophylline polymer micro particles without exposing the material to high temperatures91. 48

REVIEW LITERATURE Aerosol formulation Salbutamol sulphate particles, for use in dry powder aerosol formulation, were prepared by spray drying, using a Mini spray dryer91. Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery had been prepared with a twofluid nozzle92. Micro crystals: Recently, the process received great attention in the field of micro crystals93, 94 for the preparation of dried liposomes, amorphous drugs, mucoadhesive microspheres, drying of preformed microcapsules, Gastroresistant microspheres, and controlled-release systems. Comprehensive studies have been performed on the preparation of microspheres by spray drying techniques for different purposes, like modification of biopharmaceutical properties, formulation of dry emulsions, spray dried phospholipids, nanocrystalloaded microspheres, for drug delivery, spray-dried powders formulated with hydrophilic polymers, biodegradable microspheres, and spray-dried silica gel microspheres. Eudragit RL microspheres85 containing vitamin C was prepared by Spray drying method. Spray-drying was useful for the preparation of Paracetamol encapsulating Eudragit RS/RL or Ethylcellulose microspheres86. The spray drying technique has been widely applied to prepare micro-particles of drug with polymer. When a drug crystal suspension of a polymer solution is spray-dried, microcapsulated particles are prepared, whereas spray drying of solution of polymer containing dissolved drug leads to formation of drug-containing microspheres in which the drug can be dispersed in a molecular state or as micro crystals. In both cases, the particles tend to have a spherical shape and are free flowing. These

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REVIEW LITERATURE properties are preferable pharmaceutical manufacturing process such as tabletting and capsule filling.

3.5.3 Crystallization by Freeze drying technique: Freeze-drying, also known as lyophilization, is an industrial process which consists on removing water from a frozen sample by sublimation and desorption under vacuum. Nevertheless, this process generates various stresses during freezing and drying steps. So, protectants are usually added to the formulation to protect the microparticle and microparticle from freezing and desiccation stresses. Principle of Freeze drying: Freeze drying takes place below the triple point, where liquid passes from solid phase directly to the vapor phase. The typical phase diagram shown in Figure 12 illustrates this point. Most products are frozen well below their eutectic or glass transition point (Point A), and then the temperature is raised to just below this critical temperature (Point B) and they are subjected to a reduced pressure. At this point the freeze drying process is started. Some products drug (sucrose) solutions can undergo structural changes during the drying process resulting in a phenomenon known as collapse. Although the product is frozen below its eutectic temperature, warming during the freeze drying process can affect the structure of the frozen matrix at the boundary of the drying front. This results in a collapse of the structural matrix. To prevent collapse of products containing sucrose, the product temperature must remain below a critical collapse temperature during primary drying. The collapse temperature for sucrose is -32C. No matter what type of freeze drying system is used, conditions must be created to 50

REVIEW LITERATURE encourage the free flow of water molecules from the product. Therefore, a vacuum pump is an essential component of a freeze drying system, and is used to lower the pressure of the environment around the product (to Point C). The other essential component is a collecting system, which is a cold trap used to collect the moisture that leaves the frozen product. The collector condenses out all condensable gases, i.e; the water molecules, and the vacuum pump removes all non-condensable gases.

Figure 12 A Freeze drying typical phase diagram. Stages of freeze drying A typical freeze-drying process consists of three stages; 1) Freezing 2) Primary drying 3) Secondary drying. Freezing is an efficient dessication step where most of the solvent, typically water, is separated from the solutes to form ice. As freezing progresses, the solute phase

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REVIEW LITERATURE becomes highly concentrated and is termed the freeze concentrate. By the end of freezing, the freeze concentrate usually contains only about 20% of water (w/w), or less than 1% of total water in the solution before ice formation. The freezing stage typically takes several hours to finish. Primary drying, or ice sublimation, begins whenever the chamber pressure is reduced and the shelf temperature is raised to supply the heat removed by ice sublimation. During primary drying, the chamber pressure is well below the vapor pressure of ice, and ice is transferred from the product to the condenser by sublimation and crystallization onto the cold coils/plates (<50C) in the condenser. Typically, the primary drying stage is the longest stage of freeze drying and optimization of this stage has a large impact on process economics. Secondary drying is the stage where water is desorbed from the freeze concentrate, usually at elevated temperature and low pressure. Some secondary drying occurs even at the very beginning of primary drying as ice is removed from a region, but the bulk of secondary drying occurs after primary drying is over and the product temperature has increased. Secondary drying normally takes only hours, and the opportunity for time reduction by process optimization is limited101. With an optimum freeze-drying process, the freeze-drying process is optimized for all the three stages. 1. Freezing Freezing is the first stage of freeze drying and is the stage where most of the water is removed from drug and excipients, the system separates into multiple phases, and the interfaces between ice and drug phase form. Freezing often induces many destabilizing stresses, particularly for protein drugs. These stresses include increase of drug concentration that enhances the drug-drug interaction leading to aggregation, pH change arising from crystallization of buffer salts, reduced hydrophobic interactions 52

REVIEW LITERATURE caused by the dehydration effect of ice formation that removes bulk water from the drug phase, formation of large ice aqueous interfaces, and an enormous increase in ionic strength. The introduction of the iceaqueous interfaces and pH shifts are wellknown to cause protein stability problems. The pH shift during freezing can be minimized by optimal choice of buffer salts (i.e., avoid phosphate, succinate, and tartrate) or by reducing buffer concentration to several mM. drug degradation at the iceaqueous interface can be minimized by increasing drug concentration (i.e., saturate the drugice interface) and/ or by using surfactants
68

. For a given drug

formulation, process design also plays a very important role in protein stabilization.

Cooling Rate: One practical process approach to stabilization is to minimize the surface area of ice by growing large ice crystals which can be achieved by reduced supercooling. The degree of supercooling is the temperature difference between the thermodynamic or equilibrium ice formation temperature and the actual temperature at which ice begins to form, which is usually around 10 to 25C lower but changes with cooling rate and other factors. Higher supercooling results in more/smaller ice crystals and larger ice specific surface area. Different freezing methods, like liquid nitrogen freezing, loading vials onto precooled shelves, or ramped cooling on the shelves, give different supercooling effects with normally the highest supercooling with liquid nitrogen freezing of small volumes and the lowest supercooling for the precooled shelf method103. It was reported that slow cooling (0.5C/min) caused larger supercooling effects than the precooled shelf method103. However, the precooled shelf method gave large 53

REVIEW LITERATURE heterogeneity in supercooling between vials, which is undesirable103. Normally, it is not practical to manipulate the supercooling by changing the cooling rate in a freeze dryer because the cooling rates are usually limited to less than 2C/min, and the degree of super cooling is unlikely to change within such a small range104. Freezing Temperature and Time After freezing, the formulation should be in solid state; that is, the drug phase should be below Tg_ if amorphous or below Teu if it is in the crystalline state. This condition requires the shelf temperature for freezing be set below Tg_ or Teu, and the product batch must be kept at the temperature long enough such that all solution has transformed into solid. Because of the limited thermal conductivity between vials and shelf, complete freezing requires significant time. The freez- ing time depends on fill volume; that is, the larger fill volume takes longer to fully freeze105. Annealing Anealing is simply holding the product at a temperature above the final freezing temperature for a defined period to crystallize the potentially crystalline components (usually, crystalline bulking agent) in the formulation during the freezing stage. An annealing step is frequently necessary to allow efficient crystallization of the crystalline bulking agent. 2. Primary Drying The next step of freeze drying process design is to optimize the product temperature (Tp). The product temperature, which depends on the properties of formulations, shelf temperature and chamber pressure of the freeze dryer, and container system, cannot be directly controlled during primary drying. Therefore, it is difficult to optimize the freeze-drying process for a given pharmaceutical formulation even when its Tc and 54

REVIEW LITERATURE Tg_ are known. Because primary drying normally consumes the largest fraction of the freeze-drying cycle time, optimization of this portion of the process has significant economic impact (106). Even with highly skilled development scientists, optimization of primary drying can require a number of time-consuming experimental studies. Consequently, many formulations are freeze dried using conditions that are far from optimum. Non optimized freeze-drying processes may enormously increase the process time and may compromise product quality and/or produce regulatory concerns. The philosophy of primary drying is to choose the optimum target product temperature (Tp), bring the product to the target product temperature quickly, and hold the product temperature roughly constant at the target temperature throughout all of primary drying. Target Product Temperature The product temperature should always be several degrees below Tc in order to obtain a dry product with acceptable appearance. The temperature difference between Tp and Tc is called the temperature safety margin. It is well-known that high product temperature yields a fast process, with each 1C increase in product temperature decreasing primary time by about 13%105. Therefore, an optimized freeze-drying process runs with the product temperature as high as possible56. In other words, the target product temperature should be as close as possible to Tc. However, the risk of collapse is high if product temperature is too close to Tc. Consequently, the optimum target product is a compromise between safety and freeze-drying time. Chamber Pressure Primary drying is carried out at low pressure to improve the rate of ice sublimation. The chamber pressure (Pc) impacts both heat and mass transfer and is an important 55

REVIEW LITERATURE parameter for freeze-drying process design. Pc should be well below the ice vapor pressure at the target product temperature to allow a high sublimation rate. The sublimation rate is the mass of ice sublimed (g) per unit time (hour), which can be represented by Eq. (1).

where, dm/dt is ice sublimation rate (g/hour per vial), Pice is the equilibrium vapor pressure of ice at the sublimation interface temperature (Torr), and Rp and Rs are the dry layer and stopper resistance, respectively, to water vapor transport from the sublimation interface (Torrh/g)106. 3. Secondary Drying The last stage of freeze drying is termed secondary drying. In this stage, water that did not freeze is removed by desorption from the solute phase. Immediately after primary drying, an amorphous product still contains a fair amount of residual water (520% on a dried solids basis, depending on the formulation). The objective of secondary drying is to reduce the residual moisture content to a level optimal for stability, which is usually less than 1%. The shelf temperature in secondary drying is much higher than that used for primary drying.

Heating Rate and Chamber Pressure The shelf temperature should be increased slowly for secondary drying because a fast temperature ramp might cause collapse of amorphous products. Because of the fairly high residual moisture content in the amorphous product early in secondary drying and, thus, low glass transition temperature, the potential for collapse is greatest early in secondary drying. 56

REVIEW LITERATURE The Shelf Temperature and Secondary Drying Time The products should be kept at high temperature for a period sufficient to allow the desired water desorption. Usually, it is better to run a high shelf temperature for a short time than a low temperature for a long period64. The reason is that the water desorption rate decreases dramatically with time at a given temperature and times longer than 36 h at a given temperature do little to further reduce the moisture content. It is well-known that high water content normally decreases the storage stability of drugs. Therefore, the product is usually freeze dried to very low residual moisture content (about 0.5%). However, low moisture content in freeze-dried products does not guarantee best storage stability, at least for proteins and more complex biological products. On rare occasions, there is an intermediate moisture content for which the product has optimal storage stability109,
110

. If the target moisture content is an

intermediate level, design of secondary drying is more difficult. Usually, a combination of long drying times (6 h) and low shelf temperature (about 0C) are best, but the exact conditions must be determined by trial and error. Application of freeze-drying: The main use of freeze-drying in the field of colloidal nanoparticles is to improve their long-term Stability. However, freeze-drying has been applied for other objectives, as the improvement of drug association to nanoparticles, the preparation of core/ shell nanoparticles, the production solid dosage form and for the analytical characterization of colloidal systems.

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REVIEW LITERATURE To improve the stability of nanoparticles Freeze-drying as a drying method has many applications for nanoparticles technology. The literature contains many examples of such applications. The main use of freezedrying is essential for improving long term nanoparticles stability. The transformation of colloidal suspension into solid form has the advantage of preventing particles aggregation, also the degradation of polymer forming nanoparticles andthe leakage of encapsulated drug out of nanoparticles. Furthermore, freeze-drying could be transformed into another solid dosage form intended for different administration routes (parenteral, oral, nasal, or pulmonary.). It has been found that freeze-drying could stabilize fragile poly(-caprolactone) nanocapsules for six months during storage under extreme conditions of temperature and humidity. Such result has been obtained when a suitable lyoprotectant as PVP and optimized conditions of freeze-drying have been applied111. The stability of freeze-dried poly(methylidene malonate 2.1.2) (PMM 212) nanoparticles was evaluated after storage for 12 month under various storage conditions of temperature and illumination112. The results revealed that nanoparticles maintained at 40 C underwent significant alterations revealed by the suspension pH decrease, the progressive modification of the HPLC chromatogram of encapsulated components and the decrease in vitro cytotoxicity. Furthermore, the degradation of the polymer side chains and generation of carboxyl moieties could be observed. On the other hand, lyophilized PMM 212 colloidal nanoparticles conserved at room temperature or below, either in darkness or in daylight may be assumed to have a satisfactory shelf-life.

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REVIEW LITERATURE The size of freeze-dried solid lipid nanocapsules (SLN) remained stable after three months of storage under two storage temperatures: 5 C and 40 C at 75% relative humidity. The stored nanocapsules did not exhibit any oil leakage after 3 months storage113. Dehydroemetine nanoparticles for treating visceral leishmaniasis have been freezedried using glucose 5% as cryoprotectant. These freeze-dried nanoparticles could be stored at 20 C for 24 months without any modification of their size or the level of drug binding114. Finally, freeze-drying with trehalose was a good alternative to stabilize solid lipid nanoparticles loaded with azidothymidine (AZT) without any modification of their size or their drug content, because the storage of these nanoparticles at both 37 C or 4 C induces an increase in particle size and loss of AZT115. To improve the drug association to nanoparticles Freeze-drying has been also used to improve the association of polar drugs as Amikacin sulfate to the surface of hydrophobic carriers as

poly(alkylcyanoacrylate)nanoparticles116. Nanoparticles were prepared by the emulsion polymerization method from butylcyanoacrylate monomer and stabilized by dextran 70. The drug was dissolved in the polymerization medium at several concentrations; once polymerization was over the suspension was neutralized and freeze-dried in order to absorb the free drug not incorporated in the polymer matrix more efficiently. Drug loading was determined by polarization fluroimmunoanalysis and found to be about 66 g/mg. whereas, drug loading was about 5.95 g/mg for the standard procedure of loading nanoparticles without freeze-drying. The large 59

REVIEW LITERATURE difference in drug-polymer association rate when the polymer was freeze-dried shows that freeze-drying facilitates the drugpolymer Interaction. To produce solid dosage forms intended for various administration routes Freeze-drying has the advantage of producing stable solid dosage forms for various administration routes. The pharmaceutical applications of such nanoparticles oral lyophilized as a freeze-dried oral dosage form of indomethacin-loaded nanocapsules
117

. Poly(lactide acid) nanocapsules containing indomethacin has been prepared by

nanoprecipitation method. Then, a large amount of lactose as inert additive was added to build up a paste solid lyophilizate. The second step was to include a colloidal additive as Arabic gum in order to avoid settling of the suspension before freezing. Arabic gum was used as an aqueous solution and added to the suspension in order to obtain 2.5 to 10% of dry Arabic gum in the formula. These texture additives were incorporated into 10 ml of a nanocapsules suspension containing 10% glucose as cryoprotectant. Finally, the freeze-drying was applied to obtain the oral dosage form. To prepare core/shell nanoparticles Another interesting application of freeze-drying is to prepare core/shell nanoparticles
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These nanoparticles are formed of a drug-loaded lipid core composed of lecithin

and polymeric shell composed of pluronics (Pluronic or poloxamer) (poly(ethylene oxide)poly (propylene oxide)-poly(ethylene oxide) triblock copolymer. After the preparation of drug-loaded lipid core, it was freeze-dried with a solution of pluronics in presence of trehalose to induce the formation of a polymeric shell on the surface of the lipid core. Freeze-drying may enhance the adsorption of pluronics at the surface of lipid core to form core/shell nanoparticles. The formation of these core/shell

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REVIEW LITERATURE nanoparticles was confirmed by cryogenic transmittance electron microscopy, differential scanning calorimetry, and a particle size analyzer. To obtain dry product suitable for analytical characterization Freeze-drying has been used to obtain dry nanoparticles used for the analytical

determination of the drugs and the thermal analysis. Solid lipid nanoparticles (SLN) containing hydrocortisone and progesterone complexes with -cyclodextrins were freeze-dried without the addition of cryoprotectants127. A thermal analysis by differential scanning calorimetry was performed on these freeze-dried nanoparticles. Furthermore, the amount of hydrocortisone or progesterone incorporated in SLN was determined on the freeze-dried SLN by HPLC analysis. Hu et al.127 have used freezedrying to calculate the recovery of glyceryl monostearate solid lipid nanoparticles loaded with clobetasol propionate after their preparation. The recovery of SLN was defined as the weight ratio of the freeze-dried SLN to the initial loading of monostearin and drug and calculated from the following equation Recovery = analyzed weight of SLN X 100 / theoretical weight of SLN: However, this equation does not take into account the residual humidity in the final freeze-dried cake which, must be determined to have a correct estimation of SLN weight.

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REVIEW LITERATURE 3.5.4 Super cooling crystallization Super cooling crystals were prepared by melting the drug using heating mantle. The resulted solid crystals were kept at room temperature and followed by transferred to deep freezer. To find out the effect of heating on prepared crystals of drug substances. 3.5.5. Recrystallization technique Recrystallization of drug was done to find out the changes in crystal lattice, being induced by solvents, can influence the physicochemical properties of the substance. Hence the mechanical, micromeritic and dissolution properties of prepared crystals were compared with commercial sample of drug substance. 3.6 Evaluation of prepared crystals: The condition under which crystallization is carried out determines the texture of the prepared crystals, it is this texture, which then defines the functional properties of the powder bed. In order to control the reproducibility of the process, a certain number of physical properties are evaluated. Since the material methods are standard, they are only presented in tabular form in Table 2. Table 2: Evaluation of Prepared crystals by different crystallization techniques Property measured Residues solvents Water content Crystal Structure Particle shape Density Apparent Density Carrs index Gas chromatography Karl-fisher titration X-ray diffraction, FT-IR Scanning electron microscopy Pycnometer Mass of powder/Apparent volume Tapped apparent density- Apparent density ---------------------------------------- X 100 Tapped apparent density Sieve analysis/Optical microscopy/Particle size analyser Methods

Size distribution

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REVIEW LITERATURE Flowability Mechanical crystals Dissolution As per the Pharmacopoeia strength Flow rate of 100gm in a standard funnel of Tensile strength, Friability, Heckel plot

3.6.1 Optical and electron microscopies: The majority of materials having pharmaceutical interest consist of microcrystals, which are often aggregated into much larger composite structure. Microscopy is the best method for study of such aggregate species, and both optical and electron microscopies are methods of choice for such work. It is possible to study the optical crystallography of individual crystal particle, and to evaluate the aggregate species. A verity of micromeritic parameters are related to the morphology of the constituent particles making up a given powder, and such information is easily obtained through a microscopic examination of the solid. No unexpected crystal forms should be encountered either during the recrystallization or during crystallization. 3.6.2 Particle size distribution: The particle size distributions of drugs and excipients will exert profound effects on mixing phenomena, and on possible segregation in mixed materials. The distribution of particle sizes in powder material can affect powder flowability, and bioavailability of certain active drugs. Different methods are available for determination of particle size distribution of powdered solids. Simplest methods are optical microscopy and sieve analysis. 3.6.3 Fourier Transform Infrared Spectroscopy: Fourier spectroscopy can be described as the analysis of signal variation into its constituent frequency components119. Fourier transform of an optical interferogram 63

REVIEW LITERATURE providing a spectrum of absorption, emission, reflection, or photoacoustics constitutes FT-IR spectroscopy. Because of its speed, accuracy and sensitivity FT-IR spectrometers are gaining popularity over wavelength dispersive spectrometers119. The principles of FT-IR spectroscopy are different than the principles seen with dispersive spectroscopy techniques. Instead of being exposed to a varying energy of electromagnetic radiation, the sample in FTIR is subjected to a single pulse of radiation which consists of frequencies in a particular range120. For the identification of an organic compound, infrared (IR) absorption spectroscopy can provide preliminary data121. The infrared (IR) absorption spectroscopy provides a spectrum which is a plot of the percentage of infrared radiation that passes through the sample (% transmission) vs. the wavelength (or wave number) of the radiation122. Radiations which has wavenumbers in the range of 4000 cm-1 to 400 cm-1 under normal circumstances falls within the infrared region of the spectrum. The infrared spectrum can be further divided into 3 regions including far-IR (100-400 cm-1), mid IR (400-4000 cm-1) and near-IR (400-1400 cm-1)122. Samples with molecular species which possess small energy differences between various rotational states and vibrational states are capable of infrared radiation absorption. These types of molecules experience a net change in dipole moment due to the rotational and vibrational motions produced121. Values for the estimation of the characteristic absorption frequency for specific functional groups are summarized in Table 5.1 and 5.2 based on the approximation of Hookes law. 3.6.4 X-Ray Diffractometry: X-ray diffraction is a non-destructive technique122. It is presently an important analytical tool in the pharmaceutical industry for providing both qualitative and 64

REVIEW LITERATURE quantitative information about the structure of a molecule. The qualitative application is supported by the fact that all crystalline samples have a unique x-ray diffraction pattern. This method can also be used for the quantitative measurement of a crystalline compound in a mixture123. It is a predominantly powerful tool, commonly used for the characterization of crystalline materials and other pharmaceutical solids. A clear understanding and basic information about the physical, chemical and structural properties of polymeric materials, metals and other solids can be obtained with the X-ray diffraction technique123. The x-ray diffractometer follows the principle of scattering123. Fundamental information about the structure of a crystalline sample can be easily obtained with an x-ray diffractometer124. The incident beams are scattered in all directions by the plane of the crystalline solid sample, due to interaction with electrons present in the sample as it passes through90. When the scattered beams of radiation interferes with one another in both a constructive and destructive manner, it leads to the phenomenon of x-ray diffraction125, 126, 127. A crystal lattice in a crystal has unit cells which are arranged periodically with each unit cell having systematically arranged atoms within it128, 129. 3.6.5 Differential Scanning Calorimetry: Differential Scanning Calorimetry (DSC) is one of the most widely used thermal analytical method of analysis130. There are a number of thermal analysis techniques which can be employed including: Differential Scanning Calorimetry (DSC), Differential Thermal Analysis (DTA), Thermo Gravimetric Analysis (TGA), Derivative Thermogravimetry (DTG) and Evolved Gas Detection (EGD)131. These techniques are based on the principle of measuring the changes in physical properties 65

REVIEW LITERATURE of a substance as a function of temperature when that substance is subjected to a controlled temperature program132. Differential scanning calorimetry is now the most widely used method for the characterization of a solid dispersion133. Differential Scanning Calorimetry (DSC) is defined as A technique in which a difference in the heat flow (power) to the sample (pan) and reference (pan) is monitored against time or temperature while the temperature of the sample, in a specified atmosphere, is programmed134. The plot obtained from the DSC instrument is seen as a differential heating rate versus temperature or time (Joules/second or Calories/second) 135. 3.6.6 Scanning Electron Microscopy The scanning electron microscope (SEM) is one of the most versatile analytical instruments. It is commonly used for the examination and analysis of the microstructure morphology and chemical composition characterizations of solid samples136. SEM analysis is a non-destructive method of analysis. Therefore, it is possible to analyze the same materials repeatedly137. A focused beam of high-energy electrons is utilized by the scanning electron microscope (SEM) in order to generate a variety of signals at the surface of solid specimens. The signals produced by the interaction of the solid sample with electrons provides information about the sample which includes external morphology (texture), crystalline structure, orientation of material and chemical composition137. The fundamental principle of scanning electron microscopy is based on a variety of phenomenon. In SEM the accelerated electrons carry a significant amount of kinetic energy. This kinetic energy is dissipated in the form of a variety of signals which are produced by the interaction between the sample and electrons when the incident electrons are decelerated in the solid sample. The 66

REVIEW LITERATURE signals which are produce by above interaction includes secondary electrons, backscattered electrons, diffracted backscattered electrons, photons, visible light and heat. Secondary electrons and backscattered electrons are frequently used for imaging samples. Secondary electrons are specifically used for obtaining morphology and topography of samples and backscattered electrons are specifically used for illustrating contrasts in composition in multiphase samples. Diffracted backscattered electrons are used to determine crystal structures and the orientation of the sample. Photons are used for elemental analysis139, 140. 3.6.7 Micromeritic properties: When applied to powder, micromeritic is taken to include the fields that relate to the nature of the surface making up the solid. Powder density is an important micromeritic parameter. It is the ratio of mass to volume. Three types of density are normally differentiated, which differ in their determination of volume occupied by the powder. Bulk density is measured by volume occupied by known mass of powder sample. A measurement of tapped density is normally obtained at the same time, with volume of the solid being measured after subjecting the system to a number of controlled shocks. The repeated mechanical stress causes the powder bed to pack into a smaller volume, and so it follows that the tapped density will always be higher than the bulk density. The true density of a solid is the average mass per unit volume, exclusive of all voids that are not a fundamental part of the molecular packing arrangement. It is an intrinsic property characteristic of the powder. 3.6.8 Mechanical strength: Evaluation of the mechanical characteristics of powdered solid is vitally important to the processing of these materials. Measurements conducted on consolidated materials 67

REVIEW LITERATURE are also used during the process optimization. It should be recognized that particleparticle interactions are at the center of these investigation and all the methods are designed to deduce such information. Attrition resistance method (friability test), fracture resistance methods (Tensile strength of pellet) are generally employed to assess the mechanical strengths of the granules/agglomerates. 3.6.9 Flowability: The processability of powders/ materials is greatly affected by flowability, since the material flow invariably need to be moved from place to place. Pharmaceuticals are cohesive in nature, quantification of flow characteristics are necessary. Flowability is evaluated using angle of repose, angle of spatula and angle of fall. Carr has described a system, Carrs index that can be extremely useful in the evaluation of the flowability of the solids. 3.6.10 Ultraviolet-Visible Absorption Spectroscopy Ultraviolet-visible (UV-Vis) absorption spectroscopy involves photon spectroscopy which includes measurement of the wavelength and absorption intensity of a sample in the UV-visible region of the electromagnetic spectrum. In this spectroscopic method light in the visible, adjacent near ultraviolet and near infrared region of electromagnetic spectrum is used for excitation of electrons to a higher energy level. Upon absorption of radiation in this region of the electromagnetic spectrum, molecules undergo electronic transitions141, 142. 3.6.11 Dissolution Testing Bioavailability of drugs and bioequivalence studies between two drugs is a topic of prime importance over the past few years. This led to the development of a process called dissolution testing. Dissolution testing is used for screening new product, 68

REVIEW LITERATURE monitoring the process of manufacturing as well as the formulation of products and to perform bioequivalence studies between different batches of product143,
144

Dissolution testing is also used to determine the physicochemical consistency of the product from batch to batch since it is an inexpensive indicator. In order to determine the bioequivalence of the product and its overall pharmacological action, data obtained from dissolution rate experiments are extensively used145. 3.7 Examples of solvents Solvents employed to prepare spherical crystals can be classified as good solvent (solvent in which drug is freely soluble), poor solvent (solvent in which the drug is poorly soluble or insoluble) and bridging solvent (solvent partially soluble in both good solvent and poor solvent). Albert H L. Chow and Molly W.M. Leung146 have carried out a study of the mechanism of wet spherical agglomeration of pharmaceutical powders and proposed general guidelines for spherical agglomeration of powders.

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REVIEW LITERATURE 3.7.1 Good solvents: Isopropyl alcohol (IPA): Posses solvent properties similar to those of ethyl alcohol and is used in a number of pharmaceutical manufacturing operations. It has the advantage over ethyl alcohol in that the commonly available product contains not over 1% of water, while ethyl alcohol contains about 5% water, which is often a disadvantage147. Tetrahydrofuran (THF): It is clear colourless flammable liquid. It has dielectric constant of 7.6 and miscible with water, alcohol, ethers, esters and hydrocarbons. Its dipole movement is 1.63 debye units. THF has an odor similar to its chemical cousin, diethyl ether, but is a much less potent anesthetic than diethyl ether148. Dimethylformamide(DMF): Dimethylformamide is an organic compound with the formula (CH3)2NC(O)H.

Commonly abbreviated as DMF (though this acronym is sometimes used for dimethylfuran), this colourless liquid is miscible with water and the majority of organic liquids. DMF is is a common solvent for chemical whereas technical grade reactions. or Pure

dimethylformamide

odorless

degraded

dimethylformamide often has a fishy smell due to impurity ofdimethylamine. Its name is derived from the fact that it is a derivative of formamide, the amide of formic acid. Dimethylformamide is a polar (hydrophilic) aprotic solvent with a high boiling point. DMF is miscible with water in all proportions. The vapour pressure at 20C is 3.5hPa
149

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REVIEW LITERATURE 3.7.2 Poor solvents for hydrophobic drugs Water: Water is a very unique solvent. Besides being a highly associated liquid, giving rise to its high boiling point, it has high dielectric constant. The aqueous solution of non polar molecule is not a favorable process, which is not only due to an unfavorable enthalpy change but may also be due to an unfavorable entropy change generated by water structuring. Such an unfavorable entropy change is quite significant in the solution process. 3.7.3 Bridging solvents Chloroform: Chloroform is weak dipolar solvent but is generally considered non polar in character. It is soluble in 210 volumes of water and is miscible with alcohol, ether, benzene and with fixed oils and volatile oils. It is an excellent solvent for alkaloids and many other organic chemicals. Chloroform has a multitude of natural sources, both biogenic and abiotic. It is estimated that greater than 90% of atmospheric chloroform is of natural origin150. Isopropyl acetate: Isopropyl acetate is an ester, an organic compound which is the

product of esterification of acetic acid and isopropanol. It is a clear, colorless liquid with a characteristic fruity odor. 23 parts of isopropyl acetate is soluble of in water at 270C and is miscible with alcohol and ether. It is a good solvent for cellulose derivatives, plastics, oils and fats. Isopropyl acetate is quite flammable in both its liquid and vapor forms, and it may be harmful if swallowed or inhaled151. Dichloromethane: Dichloromethane (DCM) or methylene chloride is an organic compound with the formula CH2Cl2. This colorless, volatile liquid with a moderately sweet aroma is

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REVIEW LITERATURE widely used as a solvent. Although it is not miscible with water, it is miscible with many organic solvents152. Toluene: Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzenederivative, i.e., one in which a single hydrogen atom from a group of six atoms from the benzene molecule has been replaced by a univalent group, in this case CH3. It is an aromatic hydrocarbon that is widely used as an industrial feedstock and as a solvent. Like other solvents, toluene is sometimes also used as an inhalant drug for its intoxicating properties; however, inhaling toluene has potential to cause severe neurological harm. Toluene is an important organic solvent, but is also capable of dissolving a number of notable inorganic chemicals such as sulfur,[4] iodine, bromine, phosphorus. and other nonpolar covalent substances153.

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REVIEW LITERATURE 3.9 Drugs under study 3.9.1. Drug profile of Ketoprofen

2- (benzoyl-3-phenyl) propionic acid Chemical structure of ketoprofen Molecular formula: Molecular weight: Solubility: C16 H14 O3 254.29 Soluble in chloroform, ISO PROPYE ALCOHOL, sparingly soluble in ethanol (95%) and in ether, acetone; practically insoluble in water. Description: tasteless powder with an irritant dust. pKa: IUPAC name: Melting range: UV spectrum: IR Spectrum: 2970, 2930, 2880, 1695, 1595, 1580, 1455,1440, and 1370. 4.45 2- (benzoyl-3-phenyl) propionic acid Melts between 91-960 C In pH 7.4 is 260nm. Principal peaks at wave numbers 3200-2500, 3020, A slightly coloured, crystalline powder; odourless,

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REVIEW LITERATURE 3.9.2. Drug profile of Mefenamic acid

Chemical structure of mefenamic acid Molecular formula: Molecular weight: pKa: Melting point IUPAC name: Description: C15H15NO2 241.3 4.2 1700 C form1 and 233 0 C for form 2 2-(2,3-dimethylphenyl) aminobenzoic acid White or grayish-white, microcrystalline powder, odourless to almost odorless. Solubility: Sparingly soluble in ether; slightly soluble in ethanol (95%) and in chloroform practically insoluble in water. Soluble 1 in 25 alcohol; soluble 1 in 15 chloroform solubility in isopropyl alcohol is 15% w/v; Solubility in THF is 17.3 %w/v. UV spectrum: Acid methanol- 279nm ( A11 = 420a, 357a), 350nm; Aqueous alkali-258nm Infrared Spectrum (A11 = 420a, 322nm). Principal peak at wave number 1255,1647, 572,1504, 757,1163(KBR disk)

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REVIEW LITERATURE 3.9.2. Drug profile of Mefenamic acid Piroxicam

Chemical structure of piroxicam Molecular formula: Molecular weight: pKa: Melting point IUPAC name: C15H13N3 O4 S 331.3 5.1 & 1.8 1980 - 2000 C 4-hydroxy 2 methyl-N-(2-pyridyl)-2H-1,2-

benzothaizin-3-carboxamide -1,1-dioxide. Description: Off white to light tan or light yellow powder, odorless, colorless crystalline powder of a bitter taste. Solubility: Slightly soluble in water , in dilute acid and in most organic solvents. UV spectrum: In 0.1 M HCL 242 nm, In methanol 290 nm and 358nm. Infrared Spectrum: Principal peak at wave number 3385,3330,1635,1625, 1525, 1355, 1155, 1070, 770,730 (KBR disk)

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