M Ph (PA) IMA

Unit 2 Analysis of Drugs & Exipients in Solid State

Trainer: Chandramouli R

Introduction

normal route of administration for most pharmaceutically active agents is through the use of solid dosage forms units are produced by the formulation and processing of powdered solids regulatory bodies focus on concerns of safety and efficacy, emphasis on aspects of chemical purity Of late degree of attention being given to the physical properties of the solids that compromise a dosage form

Intro...

Ignoring the physical aspects of a formulation can be disastrous, because a variety of solid-state reactions can compromise the stability of a drug entity in its tablet matrix pathways of these reactions can be dramatically different compared with how the same reaction proceeds in the liquid or gaseous phase acquisition of of physical information allow a formulator to transcend an ability to cope with unanticipated crises

Intro...

Materials that pass the hurdles of physical test specifications would perform predictably and could, therefore, be blended, granulated, dried, compressed, and delivered into containers without operator intervention. The physical characterization of bulk drugs, excipients, and blends of them should become part of the normal process

Theory of SSA

A systematic approach to the physical characterization of pharmaceutical solids has been outlined physical properties are classified as being associated with:

the molecular level (those associated with individual molecules), the Particulate level (those pertaining to individual solid particles), bulk level (those associated with an assembly of particulate species)

study of polymorphs and solvatomorph

The nature of the crystal structure adopted by a given compound upon crystallization exerts a profound effect on the solid-state properties of that syste these variations can translate into significant differences in properties is of pharmaceutical importance

PROPERTIES ASSOCIATED WITH THE MOLECULAR LEVEL

those material characteristics that theoretically can be measured for a small ensemble of individual molecules molecular properties are often determined at the earliest stages of drug development molecular level techniques are spectroscopic in nature

Ultraviolet/Visible Diffuse Reflectance Spectroscopy

except single-crystal transmission work, most solids are too opaque to permit the conventional use of ultraviolet/visible (UV/VIS) electronic spectroscopy. Hence diffuse reflection techniques are used in:

study the reaction pathways of various solid-state reactions fields of color measurement and color matching, areas- applied to the coloring agents used in formulations successfully used in the characterization of many solid-state reactions useful in the study of drug-excipient interactions, drug degradation pathways, and alterations in bioavailability owing to chemisorption of the drug onto other components in the formulation

Vibrational Spectroscopy

energies associated with the fundamental vibrational modes of a chemical compound lie within the range of 4004000 cm1 corresponds to mid-infrared electromagnetic radiation. can be observed directly through their absorbance in the infrared region of the spectrum;

Fourier-transform infrared spectroscopy (FTIR) is now the method of choice. Raman spectroscopy, where the inelastic scattering of incident energy is used to obtain vibrational spectra

FTIR spectra are used to evaluate the type of polymorphism that exists in a drug substance and useful to study the water contained within hydrate species. Solidstate IR absorption spectra often are obtained on powdered solids through the combined use of FTIR and diffuse reflectance detection, and interpreted through conventional group frequency compilations vibrational modes of a compound are affected by fine details of molecular structure (i.e., polymorphism), the diffuse reflectance IR spectra of the polymorphs can be used to study this behavior

Another technique of vibrational spectroscopy Raman spectroscopy The sample is irradiated with monochromatic laser radiation, and the inelastic scattering of the source energy is used to obtain a vibrational spectrum of the analyte compounds of pharmaceutical interest are of low symmetry, the Raman spectrum generally resembles the spectrum obtained using the FTIR method

NMR

ultimate molecular level characterization of a pharmaceutical material Solid-state NMR spectroscopy also can be used to study the molecular environments of nuclei because these environments vary in the differing structures associated with solvates and hydrates

PROPERTIES ASSOCIATED WITH THE PARTICULATE LEVEL

those material characteristics that effectively can be determined by the analysis of a relatively small ensemble of particle studied during early development once the drug substance is available in at least milligram quantities

Microscopy

morphology of a pharmaceutical solid is of extreme importance- exerts a significant influence over the micromeritic and bulk powder properties of the material means to obtain estimations of the particle size distribution in a powdered sample. determination can be easily made regarding the relative crystallinity can deduce crystallographic information as well. particulates can be identified based on their microscopic characteristics

optical and electron microscopies are widely used to characterize pharmaceutical solids Optical microscopy is limited to the range approximate upper limit of 600. Electron microscopy work can be performed at extraordinarily high magnification levels upto 90000X two microscopy methods are complementary in that each can provide information inaccessible to the other.

Electron microscopy yields excellent topographic and shape information When polarizing optics are used in light microscopy, the optical properties of the crystals under investigation also can be determined This method can yield several directly measured parameters, such as the sign and magnitude of any observed birefringence, the refractive indices associatedwith each crystal direction, the axis angles, and the relationships among the optical axes.

Scanning electron microscopy (SEM) is the technique of choice to obtain information at high magnification levels or when a threedimensional view of a particle surface is required.

X-Ray Diffraction

primary method for obtaining fundamental structural information on crystalline substances. determine the structures of single crystals, direct method for obtaining bond lengths and bond angles for molecules in the solid state Helps to find existence of polymorphism (the ability of a molecule to crystallize in more than one structure of the same degree of solvation) or solvatomorphism (the ability of a molecule to crystallize in different structures that in turn differ in their solvation states)

for routine evaluation of the crystalline state of powdered solids x-ray powder diffraction (XRPD) is useful

Thermal Methods of Analysis

Property of the analyte is determined as a function of an externally applied temperature. sample temperature is increased in a linear fashion, while the property in question is evaluated on a continuous basis used to characterize compound purity, polymorphism, solvation, degradation, and excipient compatibility used to monitor endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, and chemical degradation) as well as exothermic processes (crystallization and oxidative decomposition). useful during the conduct of preformulation studies, because carefully planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation

Differential thermal analysis (DTA) represents an improvement to the melting point determination in that the difference in temperature between the sample and a reference is monitored as a function of temperature useful to deduce the temperature ranges associated with a variety of thermal events, as well as to assign the endothermic or exothermic nature of these reactions

Differential scanning calorimetry (DSC) represents an improvement to DTA analysis, In the DSC method, the sample and the reference are kept at the same temperature and the heat flow required to maintain the equality in temperature between the two is measured.

Thermogravimetry (TG), where the thermally induced weight loss of a material is measured as a function of the applied temperature Restricted to studies that involve either a mass gain or loss (usually loss), and is most commonly used to study desolvation processes and compound decomposition

PROPERTIES ASSOCIATED WITH THE BULK LEVEL

those characteristics of a solid that can be measured only for a large ensemble of particles once a solid formulation has reached the bulk manufacturing stage, the bulk physical properties are of importance

Particle Size Distribution

exerts profound effects on mixing phenomena and on possible segregation in mixed materials distribution of particle sizes in a powdered material can affect the bioavailability of certain active drugs,and exerts a major effect on powder flowability Optical microscopy (usually combined with image analysis), sieve analysis, laser light scattering of suspended particles, and electrical zone sensing