In the first post in this series on pharmaceutical specifications, I mentioned that characteristics or quality attributes of the active pharmaceutical ingredient (API) are generally divided into those that must always be controlled (appearance, identification, assay, impurities, etc.) and those, mainly solid state or crystalline properties of the API, that should be considered for control depending on the type of dosage form in which the API will be formulated and the manufacturing process that will be used for the final product. Drug substances may exist in different crystalline forms, which are referred to as polymorphs, and at any given temperature and pressure, only one of the polymorphs will be stable. The other, less stable, polymorphs are referred to as metastable forms.
Most pharmaceutical dosage forms such as tablets, capsules and inhaled products require a stable polymorphic or crystalline form of the API. Selection of the optimal polymorph is important for both manufacturing and therapeutic effectiveness. From a manufacturing perspective, a well-understood crystallization process that produces a reproducible polymorphic form of the API will make filtration, drying and transfer more efficient and should also improve a product’s stability during storage and shipping.
The specific polymorph of the API can also have a major effect on the therapeutic efficacy of the final product as it can impact its solubility and dissolution rate, and hence, bioavailability from the solid dosage form. This is becoming increasingly important as it is estimated that 90% or more of all newly discovered APIs have low solubility1 and almost as many, i.e., up to 85%, exist in two or more polymorphic forms.2 It has also been reported that almost 50% of APIs on the market are converted to salt forms to improve their solubility and dissolution rates.3 This is because the more stable the polymorph, the poorer the water solubility. It is for this reason that many pharmaceutical products have been formulated with metastable forms of the API as these have a higher solubility, and hence, will exhibit improved bioavailability compared to the more stable polymorph of the API. Metastable forms are often also quite stable. However, a change in storage temperature, or compression during final product manufacture, or a change in crystallisation conditions during synthesis of the API may lead to the production of the more stable polymorph, which will be less soluble. The result of this will be lower bioavailability and reduced efficacy of the medicine.
The importance of polymorphism in drug efficacy is amply illustrated by the now classic textbook example of ritonavir (Norvir®), which was registered in 1996. In the first two years that it was marketed, more than 240 batches were manufactured; then suddenly in 1998, batches started to fail their dissolution specification. Unknowingly to the manufacturer, a new polymorph (Form II) has formed during the crystallisation process, which was more stable, and hence, less soluble than the original Form I. All attempts by the manufacturer (Abbott, now AbbVie) to synthesise the original polymorph failed resulting in the product being withdrawn from the market in 1998 for almost a year to reformulate it into a new formulation.4 It was estimated that the delay and withdrawal had cost the company about $250 million.5
When evaluators of national regulatory authorities review Section 3.2.S.3.1 (Characterisation) in the CTD dossier, they expect manufacturers to address the following question on polymorphism:
- Is the API known to exhibit polymorphism?
The expected answer would be “Yes, or unknown (it is very difficult to categorically say “no”). Applicants often state “No instance of polymorphism is noted for this API in the literature”. This is considered as not sufficient.
For manufacturers of multisource medicines, only identification against a reference standard is required if polymorphism is important from a manufacturing or dosage form perspective. The preferred analytical method to determine the polymorphic form is X-ray powder diffraction (XRPD). Interpretation of the resultant diffractogram is not necessary as the primary goal is merely comparison to a reference standard to confirm that the desired polymorph is used.
For new chemical entities and drug products, readers are referred to Decision Tree #4 of ICH Q6A, which provides a stepwise procedure to determine whether acceptance criteria need to be set for polymorphism.6
- Patel, Nishadh. (2021). A Review on Significance of Identifying an Appropriate Solid Form During drug Discovery and Product Development. Material Science Research India. 18. 154-170. 10.13005/msri/180204.
- Baraldi L, Bassanetti I, Mileo V, Amadei F, Sartori A, Venturi L. Quantitation of Commercially Available API Solid Forms by Application of the NMR-qSRC Approach: An Optimization Strategy Based on In Silico Simulations. Anal Chem. 2021 Jul 6;93(26):9049-9055. doi: 10.1021/acs.analchem.0c05431. Epub 2021 Jun 23. PMID: 34159790.
- Serajuddin AT. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007 Jul 30;59(7):603-16. doi: 10.1016/j.addr.2007.05.010. Epub 2007 May 29. PMID: 17619064.
- Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.;Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.;Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.;McFarland, K. Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development. Process Res. Dev. 2000, 4, 413−417.
- Li S, Liu B, Chen Z, Ou X, Rong H, Lu M. Ritonavir Revisited: Melt Crystallization Can Easily Find the Late-Appearing Polymorph II and Unexpectedly Discover a New Polymorph III. Mol Pharm. 2023 Aug 7;20(8):3854-3863. doi: 10.1021/acs.molpharmaceut.2c00994. Epub 2023 Jul 14. PMID: 37450774.
- ICH Topic Q 6 A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. https://database.ich.org/sites/default/files/Q6A%20Guideline.pdf