PREFORMULATION STUDIES IN DOSAGE FORM DEVELOPMENT

SUBMITTED BY, Maaz naqvi, Ist semester

DEFINITION
Preformulation testing is the first step in the rational development of dosage forms of a drug substance. It can be defined as an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass-produced

PREFORMULATION COMMENSES WHEN A NEWLY SYNTHESISED DRUG SHOWS SUFFICIENT PHARMACOLOGIC PROMISE IN ANIMAL MODELS TO WARRANT EVALUATION IN MAN.

To formulate stable and effective dosage form thus giving the NCE highest possible success. To facillitate drug property based designs. Understanding problems such as molecules weakness, decay mechanism or the drug composition occuring during formulation and thus can be eradicated. To improve drug bioavailability Reduce drug excipient incompatibility

1.BULK CHARECTERIZATION :

Crystallinity and polymorphism Hygroscopicity Fine particle charecterization Bulk density Powder flow properties

2. SOLUBIITY ANALYSIS :Ionisation constant- pka pH solubility profile Common ion effect Ksp Thermal effects Solubilization Partition coefficient dissolution

3. Stability analysis :Stability in toxicology formulations Solution stability pH rate profile Solid state stability Bulk stability compatibility

BULK CHARECTERIZATION

- Polymorphism is the ability to crystallize as more than one distinct crystalline species. - crystals are characterized by repetitious spacing of atoms or molecules in three dimensional array. Amorphous forms have them randomly distributed.

1. Properties that depend on the form crystallinity : Dissolution rates Compressibility polymorphism : Melting point Density Crystal shape Optical properties Vapor pressure

2. Identification of the polymorphic form which remains stable at room temperature and within the temperature and pressure ranges applied during manufacturing. 3. Manufacturing should be done in the form which remains stable throughout the shelf life and does not change into the other more stable form.

Microscopy Fusion methods Differential scanning calorimetry IR spectroscopy X ray diffraction Scanning electron microscopy Thermogravimetric analysis Dissolution analysis

Ritonavir has two polymorphic forms viz form1 and form 2. Previously form 1 was only known and thus was the only form in which ritonavir was manufactured. Later it was found that form 1 was being converted to some other unknown form because it was more stable. Later the meta stable form 1 although more soluble, was converted to more stable form 2 for production.

HYGROSCOPICITY

The property of a chemical entity by the virtue of which it absorbs atmospheric moisture is called hygroscopicity. Absorption and equilibrium moisture content can depend upon the atmospheric humidity, temperature, surface area, exposure and the mechanism for moisture uptake.

1.Selection of excipients 2.Maintenance of the immediate environment

1. Samples of drug are kept in open containers with a thin powder bed to assure maximum exposure. These are then exposed to a range of relative humidities. Moisture uptake is then monitered. 2. Analitical methods :

Gravimetry TGA Karl fischer titration Gas cromatography

An anti TB fixed dose combination containing isoniazid and ethumbutol hydrocloride in the ratio 30:70 was found to be losing its physical stability due to moisture absorption. Research showed that the degradation was faster in the combination than in the individual drugs separately.

1. Dissolution rate 2. Bioavailability 3. Content uniformity 4. Sedimentation rate 5. Floculation rate 6. Taste 7. Texture 8. Color 9. Stability 10. Oral absorption profile

1. 2. 3. 4. 5.

Sieve analysis Air elutriation analysis Photo analysis Optical counting methods Electro resistance counting methods a) coulter counter method b) HIAC counter method 6. Sedimentation techniques 7. Laser diffraction methods 8. Acoustic spectroscopy or ultrasound attenuation spectroscopy

Nimesulide is micronized (particle size less than 5 micron) in Nimulid MD to improve its solubility and then dispersed in a highly soluble matrix with a unique combination of rapidly soluble polyols. In the case of aspirin size reduction cannot be done beyond a limit as it is irritant for the gut mucosa.

Density can be defined as the ratio of the mass of an object to its volume. Therefore, the density of a solid is a reflection of the arrangement of molecules in a solid

1. True particle density is when the volume measured excludes both open and closed pores, and is a fundamental property of a material. 2. Apparent particle density is when the volume measured includes intraparticulate pores. 3. Effective particle density is the volume seen by a fluid moving past the particles. It is of importance in processes such as sedimentation or fluidization but is rarely used in solid dosage forms.

1. 2. 3. 4. 5.

Selection of excipients Selection of capsule size Computation of porosity of packed powder beds Determination of consolidation behavior (powder compaction) determination of rate of creaming or sedimentation

Using graduated cylinder ( without tapping for bulk density and with tapping for true density). For true density only

Displacement of a liquid Displacement of a gas Floatation in a liquid

After lab scale testing, when piroxicam tablet production was scaled up, content and weight variation problem occurred in finished tablets. Later it was found that it was due to change piroxicam from one poyimorphic form to the other which had different density. Thus creating difference in densities among drug molecules and between drug and excipients, and causing segregation while mixing etc.

EFFECT ON PREFORMULATION:Selection of excipients Formulation type Manufacturing process Content uniformity Weight uniformity

Shear Cell Methods Changes in Bulk Density a) Hausner ratio = tapped bulk density/ poured bulk density b) Compressibility (Carrs index)=(tapped bulk poured)x100 density density -----------------------------tapped bulk density Avalanching Behavior Angle of repose

Poor fowability does not allow nimesulide to be prepared by direct compression. To improve its flow properties crystallocoagglomeration technology was tested, which improved nimesulides carrs index to 7-13% from 5-15%.

SOLUBILITY ANALYSIS

Amount of a substance (called solute) that dissolves in a unit volume of a liquid (called solvent) to form a saturated solution under specified conditions of temperature and pressure. Solubility is expressed as moles of solute per 100 grams of solvent.

HPLC Reverse phase HPLC UV spectroscopy Fluorescence spectroscopy Gas cromatography

Preformulation solubility studies focus on drug solvent systems that could occur during the delivery of a drug candidate. Usefull solubility values are those in a) distilled water b) 0.9% NaCl c) 0.01M HCl d) 0.1M HCl e) 0.1M NaCl All at room temperature as well as at pH 7.4 at 37 degree celcius

OBJECTIVE:Determination of pKa is important since solubility and consequently absorption depends upon dissociation constant. The unionised drug molecule is the species absorbed from GIT. By pKa determination we get to know which drug will ionise at what pH. Acidic drugs ionise in alkaline environment of intestine, and vice versa.

METHODOLOGY pKa can be dettermined by Henderson hasselbalch equation for acidic compounds:pH= pKa + log (ionized / unionised) drug drug for basic compounds:PH= pKa + log (unionized / ionized) drug drug

METHODOLOGY Analytical methods:1. 2. 3. 4.

UV spectroscopy Visible spectroscopy Potentiometric titrations The dependence of solubility on pH ( for insoluble drugs)

Thermal effects can be dettermined in terms of heat of solution. Heat of solution :It represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent. Mathematically, In s = - delta Hs/R (1/T) + C The temperature range for which thermal effects are dettermined should inlude 5degree celcius 25 degree celcius 37 degree celcius 50 degree celcius

If the process is endothermic i.e. delta H is +ve increase in temperature increase in drug solubility - if it is exothermic i.e. delta H is ve increase in temperature decrease in drug solubility - Drugs which are unstable to heat require refregerative storage and lyophilization (these products must be used within short periods.
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DEFFINITION:It is defined as the ratio of un-ionised drug distributed between the organic and aqueous phases at equilibrium. Po/w = (Coil/Cwater) equilibrium

OBJECTIVE:oil/ water partition coefficient is an indication of a drugs lipophilicity and its ability to cross cell membanes. Thus in any formulation the lipophilic/hydrophilic balance should always be maintained to give a perfect formulation.

DISSOLUTION

The breakdown of crystal lattice of a solid into individual ions, atoms or molecules and their transport into solvent is called dissolution.

Quality tool :helpful to assure that product quality is uniform in performance. Regulatory tool :a) biowaver b) ivivc c) SUPAC Exploratory tool:helpful in exploratory studies.

Dissolution of a drug particle is controlled by several physicochemical properties including chemical form, crystal habit, particle size, solubility, surface area and wetting properties. The dissolution rate of a drug in which surface area is constant is described by modified noyeswhitney equation:

dC/dT= DA/hV(Cs-C) If Cs>>C, W/A=kt a plot of W versus t gives a straight line with the slope equal to the intrinsic dissolution rate constant,k

By size reduction :eg. Nimesulide nimulid MD is micronised(size reduced below 5 microns)

By cosolvents :cosolvents are solvents which are miscible in both water and the drug. eg. Ethanol, sorbitol, glycerine, propylene glycol, polyethylene glycol

By solubilization :spontaneous passage of poorly water soluble solute molecules into an aqueous solution of a soap or detergent. it involves the property of surface active agents to form colloidal aggregates called micelles. surfactants with HLB value higher than 15 are best solubilizing agents. eg. Polyoxyethyline sorbitan are used to solubilize progesterone and reserpine.

By complexation :association of a water insoluble drug with a compound so that the complex becomes water soluble. eg. Tetracycline is complexed with fructose1,6-diphosphoric acid By salt formation :formation of a soluble salt by reaction of an insoluble acidic drug with a suitable base or by reaction of an insoluble basic drug with a suitable acid. eg. Erythromycin is dissolved by salt formation with Nacetyl-1asparagine.

By solid dispersion:a process where an insoluble drug, in the solid form, is dispersed in a suitable solid solvent, in the molecular form, to make it soluble. eg. Amorphous ritonavir, a water insoluble drug is dispersed in PEG. eg. keletra tablets have lopinavir and ritonavir as solid dispersion which is done by hot melt extrusion method.

STABILITY ANALYSIS

these studies include both solution and solid state experiments under conditions typical for the handling, formulation, storage, and administration of a drug candidate. high performance liquid cromatgraphy is the analytical method of choice for this.

Since toxicology studies typically commence early in drug development, it is often advisable to evaluate samples of the toxicology preparations for stability and potential homogeneity problems.

Usually a drug is administered to the animals in their feed or by oral gavage of a solution or suspension of the drug in an aqueous vehicle. Water, vitamins, minerals, enzymes and a multitude of functional goups, present in feed can severely reduce the shelf life of a drug. Thus, a fresh sample of feed to be used in toxicology test provides the most relevant stability data

Since enzyme activity and mobility of adsorbed water vary substantially with temperature, storage temperature typical of the toxicology lab is used for the stability study. Solution and suspension should be stored in flame sealed ampules at various temperatures. Suspensions should be subjected to an occasional shaking to check dispersibility

The primary objective of this phase of preformulation research is identification of conditions necessary to form a stable sollution.

These studies should include the effects of pH, ionic strength, co solvent, light, temperature and oxygen. Probing experiments to confirm decay at extremes of pH and temperature. Estimation for maximum rates of degradation

STUDY OF STABILITY FROM PHOTOLYSIS

Once the stability solutions are prepared, aliquots are placed in flint glass ampoules, and stored at constant temperatures not exceeding the boiling point of the most volatile cosolvent or its azeotrope. Some of these solution samples should be subjected to a light stability test, which includes protective packaging in amber glass bottles

Flow chart showing photolysis analysis

STUDY OF STABILITY FROM OXIDATIVE DAMAGE Some of the solution samples should be subjected to testing 1. with an excessive headspace of oxygen 2. With a headspace of inert gas 3. With an inorganic antioxidant 4. With an organic antioxidant

Generation of a complete pH rate profile to identify the pH of maximum stability To generate a pH rate profile stability data generated at each pH and temperature condition are analysed kinetically to yield the apparent decay rate constants. All of the rate constants at a single temperature are then plotted as a function of pH.

An arrhenius plot is constructed by plotting the logarithm of the apparent decay rate constant vs the reciprocal of the absolute temperature. If this relationship is linear, one may assume a constant decay mechanism over this temperature range and calculate activation energy by In k = -Ea/R(1/T)+c A nonlinear arrhenius plot suggests a change in the rate limiting step of the reaction or a change in decay mechanism, thus making extrapolation unreliable.

Shelf life (t10%) for a drug may be calculated from the appropriate kinetic equation, and the decay rate constant. For a first order decay process: t10%=-In 0.09/k1=0.105/k1

The primary objectives of this investigation are identification of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulation.

Weighed samples are exposed directly to a variety of temperatures, humidity and light intensities for upto 12 weeks. For surface oxidation test, samples are stored in large vials, headspace flooded with dry oxygen. If humidity is not a factor in drug stability, arrhenius plot, if linear gives shelf life. If humidity effects drug stability, data obtained at various humidities may be linearized with respect to moisture. kH=[gpl]xko

COMPATIBILITY WITH EXCIPIENTS One by one appropriate excipients can be blended with the drug at levels that are realistic. Blend is divided into weighed aliquots which are tested for stability at some elevated temperature that is lower than the melting point of the ingredients.

Check is done for possible incompatibilities arising from a multicomponent formulation Check is done for crystallinity, polymorph conversion, and solvate formation.

1. MODERN PHARMACEUTICS By Banker And Rhodes 2. THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY BY LEON LACHMAN 3. DRUG DOSAGE FORM AND DRUG DELIVERY SYSTEM DESIGN 4. www.sciencedirect.com 5. www.wikipedia.com 6. www.pubmed.com

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