![]() ![]() The free energy relationship between two polymorphs may be determined by DSC. The free energy landscape between any two polymorphs is represented as in Fig. Two polymorphs are related enantiotropically if T t lies below the melting temperatures of both forms otherwise, they are monotropically related. The relationship could also be explained in terms of the transition temperature, T t, which is the temperature where the two forms are in thermodynamic equilibrium (or change in free energy, Δ G=0). On the contrary, if one polymorph is always more stable at all temperatures (below the melting temperature), they are said to be related monotropically. In the temperature domain, an enantiotropic relationship exists if one form is more stable under one temperature range and the other more stable under another, that is, their conversion is thermodynamically reversible. Two polymorphs may be thermodynamically related as enantiotropes or monotropes. However, the incorporation of a metastable form may have significant implications to the dosage form design, manufacturing, storage, and regulatory compliance. Metastable forms could be used, and in some cases, they may be beneficial to the manufacturing process or in vivo performance. A thermodynamically more stable form is often preferred due to the less likelihood of phase transformation in general. An important topic in polymorph characterization is to delineate the thermodynamic relationship among the different crystal forms. Polymorphs represent the local minimums in the free energy landscape of the crystalline molecule. Hence, agencies generally require that crystal forms of a drug substance be examined carefully against the properties that may be relevant to the dosage form design, process development, manufacturing, and in vivo performance of the product and implement appropriate controls to safeguard the identity, strength, quality, purity, and potency of the drug product. 26,27 Polymorphs can have a significant difference in solubility, stability, mechanical properties, and thermal properties and thus may impact formulation, manufacture, and performance of pharmaceutical products. Organic molecules including drugs are notorious for their formation of multiple crystalline forms. In the previous section on PXRD, it was discussed that polymorphism is the existence of more than one crystal packaging by the same molecule entity. Zhou, in Developing Solid Oral Dosage Forms (Second Edition), 2017 3.4.1.2.2 Characterization of polymorphs Disorder leads to peak broadening in the in the powder pattern, and eventually an amorphous “halo.” This also means that conversion to amorphous phases in APS studies is not detectable by PXRD, other than by loss of the ingoing API.ĭ. PXRD can be used as a qualitative and sometime quantitative assessment of the degree of crystallinity of the pure API. In addition, the API peaks must be distinguishable from any crystalline excipient peaks. This relies on the presence of detectable diffraction peaks of both the ingoing API form and the forms to which it may convert at the formulated levels. For this reason, PXRD of the API can be done in controlled environmental conditions, using hot stage and/or controlled humidity environments to simulate APS conditions in order to assess risk of any form conversions (e.g., hydration/dehydration).įurthermore, it can be used to determine if any change in crystalline form (e.g., hydration, salt disproportionation) in the drug product has occurred during the APS study. Each polymorph, salt, or cocrystalline material will have its own specific pattern. Each API will produce a specific pattern depending on the structure of its crystal lattice. Powder X-ray diffraction (PXRD) measures the diffraction pattern of crystalline material. Swanson, in Accelerated Predictive Stability, 2018 3.2 Powder X-Ray Diffraction (PXRD) ![]()
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