ABSTRACT
Preformulation testing entails all studies conducted on a drug substance towards generating practical data for the successful fabrication of a stable and biopharmaceutically apt drug dosage form. Pharmaceutical preformulation investigations can have an enormous impact on drug discovery and product development as they reveal important data with respect to the intrinsic and extrinsic properties of a drug substance and its suitability to be formulated into a medicinal dosage form. Moreover,
6.1 Introduction .................................................................................................. 163 6.2 Process of Preformulation ............................................................................ 164
6.2.1 Preliminary Information ................................................................... 165 6.2.2 Parameters for Primary Evaluation .................................................. 166
6.2.2.1 Organoleptic Properties ..................................................... 166 6.2.2.2 Crystal Properties (Particle Size, Shape and Crystallinity) ... 166 6.2.2.3 Polymorphism .................................................................... 168 6.2.2.4 Thermal Analysis Profile ................................................... 169 6.2.2.5 Hygroscopicity ................................................................... 169 6.2.2.6 Partition Coefficient ........................................................... 170 6.2.2.7 Permeability ....................................................................... 170 6.2.2.8 Solubility ............................................................................ 170 6.2.2.9 pKa ...................................................................................... 173 6.2.2.10 Intrinsic Dissolution ........................................................... 174 6.2.2.11 Stability .............................................................................. 175 6.2.2.12 Particle Density and Compressibility ................................ 176 6.2.2.13 Flow Properties .................................................................. 176
6.3 Compatibility Studies ................................................................................... 177 6.4 Dosage Form-Specific Studies ..................................................................... 183 6.5 Conclusion .................................................................................................... 183 References .............................................................................................................. 184
tion. Before the development of any dosage form of a drug substance, it is crucial that particular fundamental physical and chemical properties of a drug substance are determined. Interestingly, the application of high-throughput technologies in previous years has expedited drug substance screening and selection, permitting useful compilation of physicochemical properties (Chen et al. 2013). These properties form the basis for fabricating a drug’s combination with appropriate pharmaceutical excipients for producing the right dosage form. This information may also influence many of the ensuing processes in formulation development, such as manufacturing methods and conditions. This preliminary stage of evaluation is described as the preformulation phase and is at the interface between the drug entity and formulation development. Pharmaceutical preformulation spans across disciplines and is construed differently by different groups in an industrial research setting. For instance, medicinal chemists can manipulate structural traits of potential drug candidates on the basis of information received on the stability, solubility and cell penetrability from preformulation studies, whereas pharmacologists can use the same information to determine drug therapeutic and toxic levels, and pharmaceutical analysts can optimise assay procedures for determination of the drug substance/product. After drug candidate selection, further along the developmental stages, preformulation studies provide insight to large-scale manufacturing, dosage form development and clinical investigation processes. Drug substance manufacturers utilise information on salt form, purity and yield to control drug production and formulators integrate preformulation data such as drug physicochemical characteristics for designing a suitable dosage form for drug delivery by appropriate excipient selection and opting for the right processing conditions. Information on physicochemical properties such as solubility and permeability of drug substances, obtained from preformulation studies, can provide insights into pharmacokinetic and pharmacodynamic behaviour of the drug substances. Preformulation begins after extensive literature survey of identical or similar types of compounds. It provides an understanding of the relationship between physicochemical properties of the drug substance and its bioavailability, potential degradation, side effects/toxicity of formulation components, and helps select the appropriate dosage forms.
