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Ensuring Consistency in Polymorphic Drug Substances and Products

Dr Edislav Lekšić of Almac Group explains how qualitative and quantitative phase analyses ensure product quality in all phases of drug development. Polymorphs and their properties Consistency in production is a requirement for active pharmaceutical ingredients (API) as well as final dosage forms.1 However, drug molecules are prone to exhibit polymorphism, due to a variety of supramolecular arrangements – based mostly on hydrogen bonding networks generated from different functional groups.2 A variety of non-covalent bonds of different strength and polarity may impact the physical properties of the final powder or API, including wettability, solubility or dissolution rate, or even chemical stability (Figure 1). In addition, some bulk powder properties such as tapped density and tablet performance can be influenced by polymorphic form.

In fact, numerous steps in the production of a targeted form have the potential to cause transformation, including filtration, drying, micronization or during storage. Preventing such transformations between polymorphs is critical for process robustness and product safety. Faster polymorphic transformation is generally associated with wet systems, as liquid enhances API solubility and molecular mobility. In some cases, it is impossible to develop a drug in a pure polymorphic phase.3 If transformation is slow and there are no significant differences in solubility or performance of the two polymorphs, these batch mixtures may be acceptable, provided there is a suitable method to monitor transformation over time. In such cases, polymorphic stability of the batch is used to determine the API’s shelf-life. Stability is also influenced by the excipients added during formulation of a drug product. APIs are almost always mixed with excipients in final dosage forms of tablets, capsules, creams or suspensions. The formulation process often involves high-energy activities like dry or wet granulation, spray drying or melt extrusion. Once formulated, it is still possible to monitor potential polymorphic transformations using a suitable method for solid state characterisation, such as X-ray powder diffraction (XRPD).

Regulatory requirements

Figure 1 – Hypothetic and schematic presentation of two polymorphs and the impact on kinetics of solubility

Polymorphic transformation Often, the existence of a small energy difference between polymorphs can allow a transformation to occur, even at room temperature, in the solid state or in a suspension. This energy difference can be overcome by applying mechanical stress, for example during micronization of the API or by a higher level of residual solvent in API crystals before storage.

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It is becoming very important to quantify crystalline phases precisely and accurately, to satisfy regulatory concerns about the safety and efficacy of drug substances and products. Manufacturers are required, as part of their applications for new investigational drugs and submissions for marketing approval in both the US and EU, to provide data on whether changes in a drug substance or drug product affect performance. Guidelines from the International Conference on Harmonization, ICH Q2 (R1) specify that manufacturers must have validated and reproducible methods for characterizing and controlling polymorphs throughout a drug’s shelf-life.4 ICH guideline Q6A specifies the use of XRPD to characterize and monitor crystalline forms as an acceptance criterion for new drug substances and drug products.5

Speciality Chemicals Magazine October 2017  
Speciality Chemicals Magazine October 2017  

Volume 37, Issue 05