Understanding the solid form of a drug molecule is fundamental to developing robust drug development strategies, as it can affect the efficacy of the final pharmaceutical product, as well as the material handling characteristics during its manufacture.

The various different crystal lattice packing arrangements of the same active pharmaceutical ingredient (API) molecule are referred to as polymorphs, and these packing arrangements can be modified by salt, cocrystal, hydrate and solvate formation. The importance in understanding these variations is crucial, as differences in API physical properties can lead to variation in bioavailability, while the intellectual property (IP) of a drug substance can be exploited if the polymorphs of an API are not protected in a patent submission.

Physical properties of interest to solid state chemists and formulators include packing properties of materials, such as molar volume and density; thermodynamic properties such as melting point, enthalpy, free energy and chemical potential; as well as the resulting thermodynamic activity of compounds and their solubility.

Additionally, the kinetic parameters of the solid dosage form including dissolution rate and the stability of the solid form are highly important from a biopharmaceutical point of view. Related to these are the surface properties of the components of the dosage form including surface free energies, interfacial tensions, hygroscopicity and the size of the particles, while mechanical properties such as hardness and compactibility also have a significant effect on the dissolution properties of solid forms.

The Biopharmaceutics Classification System (BCS)¹ is a system used to differentiate drug substances based on their solubility and permeability, and this is shown in Table 1. Many new chemical entities (NCEs) are BCS Class II or IV, which have low solubility, while Class I APIs have preferred solubility and permeability characteristics. The solubility of Class II APIs may be improved by a salt or cocrystal version of the API, while the solubility of Class IV APIs might be improved by combining the solid with an adsorption enhancer and/or through particle size reduction. For Class III solids the formulation may often include the use of an adsorption enhancer, such as PEG 300 or cyclodextrin.

Crystallization
For all classes of product, crystallization is usually the final step in an API’s manufacture. For an efficient crystallization process, high chemical purity, confirmation that the correct form of the API is present, and it has a suitable particle size and shape to ensure suitable downstream processing into the drug product must be achieved.

The characteristics and properties of an API also influence the efficiency of manufacturing operations such as filtration and drying, as well as secondary processing such as milling. The correct initial solid form must be achieved before further processing, so it is crucial that the crystallization process can be controlled in order that a process will reproducibly afford the same, desired API with a quality profile to meet specification.

Carrying out solid form investigations early in development are a balance between the cost of development and the risk of progressing what turns out to be an unsuitable version for development. As Figure 1 shows, solid form investigations act as a bridge between API manufacturing and formulation development, and carrying out studies at an early stage can save time and expense in having to solve issues later on in development, helping to create a dosage form that can afford the greatest chances of success in early clinical trials.


Salt/cocrystal investigations
It is possible to alter the properties of an API without changing the pharmacologically active moiety by forming a salt of the API, or by producing cocrystal versions. This can enhance the molecule’s solubility (and offer improved bioavailability), dissolution profiles, and physicochemical properties such as thermal characteristics, hygroscopicity, propensity to polymorphism, and chemical stability. In addition, the development of a salt or cocrystal version can provide an opportunity for impurity control. Understanding polymorphism can guide initial formulation studies, the relationship between API forms, and efficacy and stability, which assist in the selection of the ideal API version candidate for development and manufacture.

The regulatory position of pharmaceutical cocrystals has been clarified by the FDA,² while the EMA distinguishes cocrystals as binary adducts.³

Crystallization development
Development of an API manufacturing process needs to maximize the yield of a product with suitable purity and particle characteristics. As a ‘bottom up’ operation, crystallization can control what version of the API is produced (hydrate, solvate, salt, cocrystal and polymorphic form), the impurity levels it contains, and the particle size distribution. Controlled crystal growth is a function of API solution saturation and crystal formation, which can be controlled by employing a seed of the API of the desired form or version.

There are a number of complex parameters that affect the properties of the final crystalline solid including nucleation rate, growth rate and growth mechanism, while the expertise of solid-state scientists is vital to understand how the concentration of the API in solution, temperature and cooling profiles affect the process, yield, and quality of the isolated API.

Bulk particle manipulation
Physical modification of bulk API particle properties is employed to improve drug product manufacture or enhance the API’s performance. As a ‘top down’ operation, bulk particle manipulation affords a particle size distribution required for effective formulation, with the target particle size being dependent upon the mode of administration and the dosage form of the drug product. Effective formulation, and maximizing a drug product’s efficacy, relies on understanding the drug substance particle properties such as shape, size, size distribution, hygroscopicity, adhesiveness, density, flowability, wettability and compaction.

Milling and micronization are key technologies in controlling the particle size of an API and affording drug substance that is optimized for formulation. Understanding and controlling particle size, and engineering the most suitable product, is an extension of API process development and solid form investigations, so that the most stable and efficacious version of an API can be progressed. Ideally, working in parallel, rather than linearly across all these development stages, and supported by analytical scientists with experience and expertise across a range of techniques, can provide rapid progress towards clinical milestones.

Case study: Salt screen development to improve API purity and solubility
An API was presented for solid form development, with the assumption that the free API demonstrated poor solubility. The goal of the program was to identify a suitable salt of the API to improve this. Initial estimates suggested a strong acid would be required, and an assessment of 24 solvents and solvent mixtures led to four solvents being considered appropriate. For the salt screen, 15 counter ions were assessed, which afforded a shortlist of four suitable salts of the API (Table 2).


These four API salts were carried forward into pre-formulation evaluation, and from the first scale-up iteration, counter ion B and C salts were isolated as the target di-salts; counter ion A salt was isolated as a di-salt and as a mono-salt during the screen; while counter ion D salt was not isolated and was therefore removed from evaluation.

Pre-formulation evaluation of the three salts including determination of solubility (Table 3) and stability (Table 4) in a range of dissolution media at 37°C and form and chemical stability under accelerated stability conditions for three weeks were undertaken.



Despite counter ions A and B demonstrating higher levels of solubility than counter ion C, there were stability concerns of counter ion version A, therefore, further development on this candidate was stopped. This left counter ion B and C versions to be progressed into polymorph screening to identify the propensity of both salts to polymorphism, and version change. The desired version would then be progressed into crystallization development. The manipulations applied during these polymorph investigations included equilibration with thermal modulation; generation of amorphous API salt versions; solvent-mediated equilibration with thermal modulation of amorphous API salt versions, saturated solution cooling crystallization, and anti-solvent-driven (cooling) crystallization.

API counter ion B di-salt demonstrated significant version change, exhibiting not only two polymorphic forms but also multiple hydrates and multiple anhydrates. There was also evidence of the presence of solvates and salt disproportionation in one of the solvents used.

In contrast, API counter ion C di-salt demonstrated little version change, with Pattern A found as the predominant and thermodynamically favored form. Two other versions were identified: Pattern B being a non-solvated form isolated from one solvent; and Pattern C also being a non-solvated form, isolated from one solvent.

The API counter ion C di-salt, Pattern A candidate was selected and progressed into crystallization development for process identification and improvement. Primary investigations covered aqueous-based recrystallization and solubility evaluation in solvent/water mixtures that identified alcohol/water mixtures as favored. A cooling crystallization based upon findings from the polymorphism investigation afforded a new polymorph, Pattern D. The solvent mixture was refined to a 9:1 alcohol/water mixture.

Direct reactive salt forming crystallizations from the selected alcohol/water were then carried out in a range of process volumes, with 10 volumes giving an 83 % recovery of product with particle size distribution and characteristics suitable for clinical evaluation.

Early investigations for accelerated development
Understanding the solid form behavior of an API early in development is crucial to ensure the success of a viable drug candidate. By investigating and being able to control the solid-state properties of an API, downstream processing will benefit from predictable stability, solubility and optimal handling characteristics of the material during manufacture. By investing time and resource into solid state investigations and leveraging the experience of specialized scientists in the field, significant advantages in particle control and drug product properties can be realized, minimizing development timelines and cost and increasing the chances of clinical success. 

References

1. Amidon, G.L., Lennernäs, H., Shah, V.P. et al. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability. Pharm Res 12, 413–420 (1995). https://doi.org/10.1023/A:1016212804288.
2. Regulatory Classification of Pharmaceutical Co-Crystals, February 2018, FDA-2011-D-0800 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/regulatory-classification-pharmaceutical-co-crystals).
3. Reflection paper on the use of cocrystals of active substances in medicinal products, 21 May 2015, EMA/CHMP/CVMP/QWP/284008/2015 (https://www.ema.europa.eu/en/use-cocrystals-active-substances-medicinal-products).