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preformulation concepts, drug excipient interactions different methods slideshare

This document discusses preformulation concepts and drug-excipient interactions. Preformulation involves investigating a drug's physical and chemical properties alone and with excipients to generate information for developing stable and bioavailable dosage forms. Drug-excipient interactions can be physical, chemical, or physiological, and are studied using techniques like thermal analysis, spectroscopy, and chromatography. Thermal methods like DSC and microcalorimetry detect interactions by examining heat changes, while spectroscopy and chromatography analyze molecular structures and separation of drug components. Understanding these interactions is important for developing optimal drug delivery systems.

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Preformulation Concepts Drug excipient interactions different Methods Presented By; Vamshi Pradeep N M pharm department of pharmaceutics
Preformulation Concepts Almost all drugs are marketed as tablets, capsules or both. Prior to the development of these major dosage forms, it is essential that certain fundamental, physical and chemical properties of the drug molecule and other properties of the drug powder are determined. This first learning phase is known Preformulation Definition:- It can be defined as an investigation of physical and chemical properties of a drug substance - alone and or when combined with excipients.
Objective  to generate information useful to the formulation in developing most stable and bioavailable dosage form that can be produced. Determine kinetic rate profile. Establish physical characteristics. Establish compatibility with common excipients. Provide insights into how drug products should be processed and stored to ensure their quality. To develop an optimal drug delivery system
This data collection include information such as: •Gross particle size • Melting point • Infrared analysis •Thin-layer chromatographic purity •And other characteristics These data are useful in guiding, and becoming part of, the main body of preformulation work.
Drug excipient interactions Changes in the physical, chemical or therapeutic properties of a dosage form resulting from the interaction of the API with excipients or other components of the drug product. An incompatibility in dosage form can result in any of the following changes: •change in colour/appearance • loss in mechanical properties (eg, tablet hardness) •changes to dissolution performance •physical form conversion •loss through sublimation •decrease in potency •increase in degradation products.
The drug-excipients interactions can be broadly classified as 1. Physical interactions 2. Chemical interactions 3. Physiological/biopharmaceutical interactions
1. Physical interactions •These types of interactions are quite common but are very difficult to detect in dosage forms. •Drug substances and excipients interact without undergoing changes involving breaking or formation of new bonds. •The components of the drug product retain their chemical structure but undergo changes which alter their physical properties. •Physical interactions may result in changes in dosage uniformity, colour, odour, flow properties, solubility, sedimentation rate, dissolution rate etc Ex , physical interaction between an API and an excipient is that between primary amine drugs and microcrystalline cellulose.
2. Chemical interactions • This involves the interaction of drug substance and excipient through chemical degradation pathway. • The formulation undergoes a chemical reaction in which the constituent atoms are rearranged via bond breakage and bond formation to produce an unstable chemical entity. • Changes in the study samples are analyzed by a chromatographic- based assessment or by any other analytical method. Ex, 1. Surfactants like TWEEN 180 and other non ionic surfactants undergoes OXIDATION and leads to degradation of proteins. 2. Co-solvent like propylene-glycol leads to HEMOLYSIS with nicotinamide and dimethylisosorbide.
3. Physiological/Biopharmaceutical Drug-excipient Interactions •These occurs after the drug product has been administered to the patient. • Excipients are included in a formulation specifically because they interact with the physiological fluids and function in certain ways e.g., disintegrants in immediate release tablets and capsule formulations
Methods for drug excipient interactions The drug excipient compatibility studies are carried out with an intent to identify, quantify and predict potential interactions (physicalor chemical) along with the impact of these interactions on the manufacturability, quality and performance of the final drug product. 1.Thermal techniques. 2. Spectroscopic techniques. 3. Chromatographic techniques.
1) Thermal techniques. • The physicochemical properties of drug substances are measured as a function of temperature. • In this method, the test samples are subjected to a controlled temperature over a given period of time. a) Differential Scanning Calorimetry (DSC) b) Isothermal Microcalorimetry c) Differential Thermal Analysis (DTA) Advantages  Requires of short time of analysis  Low sample consumption  Provides useful indications of any potential incompatibility.  It gives meaningful results without requirement of multiple sample preparations.
a. Differential Scanning Calorimetry (DSC) In this technique, the DSC curves of pure samples are compared to that obtained from 50% mixture of the drug and excipient (usually 5mg of the drug in a ratio of 1:1 with the excipient). It is assumed that the thermal properties (melting point, change in enthalpy, etc.) of blends are the sum of the individual components if the components are compatible with each other. An absence, a significant shift in the melting of the components or appearance of a new exo/endothermic peak and/or variation in the corresponding enthalpies of reaction in the physical mixture indicates incompatibility.
Advantages of DCS: ■Requires of short time of analysis. ■ Low sample consumption. ■ Provides useful indications of any potential incompatibility. Limitations of DSC: ■Conclusions based on DSC results alone may be misleading and have to be interpreted carefully. ■ DSC cannot be used if thermal changes are very small. ■ DSC cannot detect the incompatibilities which might occur after long-term storage
b. Isothermal microcalorimetry ➤This is an extremely sensitive and invaluable tool used to determine drug-excipient incompatibilities. It measures minute amounts of heat emitted or absorbed by a sample in a variety of processes. ➤In a typical drug-excipient compatibility study, a solution, suspension, or solid mixture of drug substance and excipient is placed in the calorimeter and the thermal activity (heat gained or evolved) at a constant temperature is monitored.
Advantages of Isothermal microcalorimetry ■Samples are not heated, and so the changes are observed as it might typically occur at ambient conditions. ■ It is sensitive to small changes in heat gained or evolved, thus small samples, or slow processes, may be investigated. ■ It gives meaningful results without requirement of multiple sample preparations. ■ Does not require long storage times.
C. Differential Thermal Analysis (DTA) It is an analytical technique in which the changes in temperature between a test sample and an inert reference under controlled and identical conditions is used to identify and quantitatively analyze the chemical composition of a substance. When the test sample and inert reference are heated to a sufficient temperature, the thermal changes in the test sample which lead to the absorption or emission of heat can be detected relative to the inert reference (control). The differences in temperature are then plotted against time, or against temperature.
Advantages of Differential Thermal Analysis •DTA technique yield data that are considerably more fundamental in nature. • Enthalpy change (under a DTA peak) is not affected by the heat capacity of the sample.
2. Spectroscopic techniques. a) Vibrational Spectroscopy b) Flourescence spectroscopy / Fluorometry a) Vibrational Spectroscopy  Using this method, information on the molecular structure and environment of organic compounds are generated.  These vibrations are commonly studied by infrared and Raman spectroscopies. b) Flourescence spectroscopy / Fluorometry Analyzes fluorescence properties of samples in order to provide information regarding their concentration and molecular environments
The spectra obtained are indicative of the nature of chemical bonds present in the test sample, and when pieced together can be used to identify the chemical structure or composition of a given sample. Fluorescence spectroscopy has also been used in: 1. Carrying out limit test where the impurities are fluorescent or can simply be rendered fluorescent. 2. Determination of fluorescent drugs in low dose formulations containing non- fluorescent excipients. 3. Studying the binding of drugs to components in complex formulations and measuring small amount of drugs and for studying drug-protein binding in bioanalysis.
3. Chromatographic techniques Chromatography is an analytical technique frequently used in pharmaceutical research for separating sample mixture into its individual components. a) THIN LAYERCHROMATOGRAPHY (TLC)  TLC is widely used in drug- excipient compatibility study as a confirmative test of compatibility after performing DSC.  An excipient is considered to be potentially compatible with the drug substance if the spots produced have identical Rf value
References : 1. Lachman/Lieberman's "The Theory and Practice Of IndustrialPharmacy" Fourth Edition 2013. 2. Modern Pharmaceutics Fourth Edition, Revised and Expanded, Edited By G.S.Banker & C.T.Rhodes, Marcel Dekker pg387-389. 3. Nishath Fathima, Tirunagari Mamatha, Husna Kanwal Qureshi, Nandagopal Anitha and Jangala Venkateswara Rao (2011). Drug- excipient interaction and its importance in dosage form development. Journal of Applied Pharmaceutical Science 01 (06); 2011: 66-71
4. Chaurasia G. (2016). A Review on Pharmaceutical Preformulation Studies in Formulation and Development of New Drug Molecules. International Journal of Pharmaceutical Science and research, 7(6): 2313-2320. 5. https://www.pharmapproach.com/drug-excipient- compatibility-studies/
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