Stable form screening

Stable Form Screening (slurries to identify stable polymorphs and solvates) Thermodynamics Targeted to find the most stable polymorph and stable solvates 10-20 solvents (neat or mixed) with variety in their properties and focus on those that provide high solubihty SolubUify, HBD/HBA propensity, polarity, dipole moment, dielectric constant... 

Gong, Y., CoUiman, B. M., Mehrens, S. M., Lu, E., Miller, J. M., Blackburn, A., et al. 2008. Stable-form screening Overcoming trace impurities that inhibit solution-mediated phase transformation to the stable polymorph of sulfamerazine. J. Pharm. Sci. 97 2130. 

Molecules in real solvents can exist in one or more tautomeric forms. The use of different tautomers in calculations can lead to significant variation in the estimated log P values (Pig. 15.1). Accurate prediction of the dominant tautomer requires ah initio calculahons. Due to speed limitations such calculations are not feasible for virtual screening and prediction of large compound collections. Moreover, the interpretation of the results can also be difficult, for example, the lacton-lactim (Pig. 15. IB) is the stable form of maleic hydrazide in the gas phase but the difference between this and the dilacton form (Pig. 15.1C and D) disappears in solution... 

It is clear that kinetic effects must be utilized in the design of a process to make the commercially available Form A, because it is never the most thermodynamically stable form. Information from the literature and patents in reference [14] indicates that Form A can be successfully isolated from Acetonitrile, Acetone, Methyl isobutyl ketone, Toluene, the C2 to C4 alkenols, Ethanol, Methanol and Propan-2-ol. In these solvents it is likely that solvation is favourable to the nucleation rate of Form A or detrimental to crystal growth of the other forms, or both. For a new development compound there should be similar solvent interaction data available from polymorph screening experiments. 

Neupogen), a four-helix bundle cytokine, is formulated at pH 4 but has been shown to maintain both thermal stability and tertiary structure at pH 2.60 In fact, the secondary structure of this molecule was shown to remain highly helical at pH 4 (Tm approximately 62°C) and 2 (Tm approximately 63°C) as compared to pH 7 (Tm approximately 55°C) where a less conformationally stable form was observed. In the same study, FTIR and CD data corroborated the tendency of the protein to unfold as measured by the loss of helical structure in the order pH 7 > pH 4 > pH 2. Moreover, after determining optimal pH conditions of thermostability, several studies have shown that excipient screening at such conditions can successfully predict the rank of formulation cocktails that offer the most favorable stability.14 23 31 56... 

The thermodynamically favored form of a final product is usually the most desirable crystalline form, and screening studies should define the stability of the polymorphs. A less stable form may be preferred if it displays markedly improved dissolution and bioavailability. In this case it would be necessary to ensure that the less stable form can be reliably prepared on scale before committing to preparing this polymorph exclusively. 

The greatest concern with this approach is lack of nucleation of the most stable form. If the starting API does not contain seeds of the stable form, a successful screen will produce nucleation of the stable form within the duration of the slurry experiments in at least one of the solvents. Lack of adequate solubility, or inhibition of nucleation due to solvent-solute interactions, may preclude transformation to the stable polymorph (Gu et al., 2001). Moreover, impurities or additives, even in trace amounts, can dramatically affect the rate of solvent-mediated polymorphic transformation (Gu et al., 2002 Okamata et al., 2004 Mukuta et ah, 2005). Thus, it is important to have starting API with the highest possible purity. Recrystallization prior to starting this or any type of polymorph screen can be used in an attempt to purify the API. While this could reduce an impurity that might stifle solvent-mediated transformation to the most stable polymorph, it should be noted that recrystallization from solution does not... 

It should be noted that it is possible to crystallize metastable hydrates from aqueous solution. A metastable hydrate is one that when saturated in water, where the water activity is maximal, there exists an anhydrous crystal form that is thermodynamically more stable. For a stable hydrate screen, solvent mediated conversion will occur in time, converting the metastable hydrate to the stable anhydrous form. Thus, a metastable hydrate should not be observed in a stable hydrate screen, provided the slurries have reached equilibrium. 

The screening for crystal forms ought to be directed not only to the search for the thermodynamically most stable crystalline form (which will have less tendency to transform spontaneously into a different crystal form) but also to the study of the chemical-physical properties of the various hydrates and solvates, amorphous phase, and, when necessary also to the investigation of the various salts (e.g. hydrochlorides, sulfonates etc.) forms. For instance, in view of the low solubility and bioavailability of the stable form of ritonavir, it is of interest to ask how and when the drug would have been launched if only that form had been known in the early stages of the drug s development. 

This chapter reviewed only H-bond propensity analysis approaches to complement polymorph screening by facilitating the risk assessment of a missed more stable form. A focus was given to different theoretical approaches of H-bonding ranking, which were developed to accurately reproduce experimental observations as well as high-level theoretical calculations. Successful applications of COSMO-RS and QTAIM-based methods to support the pharmaceutical solid form selection were demonstrated. 

Over the past few years, materials scientists have designed and conducted research to determine the stable form in the conditions of the formulated dosage form. Luthra et al. identified that the thermodynamically stable form, anhydrous crizotinib free base, converted to a qnatemary complex (API, phosphate, water, sucralose) in the formulated oral solution in which precipitation was observed [9]. This spurred the design of new solid form/polymorph investigation designated as the Formulation Form Screen. In this case as well as research published by Arora et al. [10, 11] and Bak et al. [12], unintended cocrystal formation occurred between the stable form of the API and the formulation components. As the number of variables and conditions exponentially increase as the stable API form is exposed to a formulated environment, there becomes a need to develop new approaches to test the reactivity of the API with its formulation components. 

An abbreviated, nonconventional, polymorph screen was conducted on sulopenem free acid. A total of eight forms of sulopenem have been discovered and are consistent with three anhydrous forms (Forms A, B, and D), one hydrate (Form C), three solvates (Forms E, F, and G), and an amorphous form. Form B was confirmed as the most stable form in the short-term slurries at room temperature (RT) and S C. This form also resulted from competitive slurries between Form B and pairings of Forms A, C, and D. Since the isothermal slurries at 5°C and RT were conducted for limited time due to rapid chemical degradation, computational methods were investigated to complement the experimental results, that is, build more confidence to establish whether or not Form B is the most stable anhydrous form. 

Crystallization experiments from solution, using several techniques (e.g., (i), (ii), (iii), and (v) in Table 5.1) with a variety of solvents and solvent mixtures. Due to the practical relevance of hydrates, water and water/solvent mixtures should always be included. Suspension equilibration and slow coohng experiments play a particular role in finding the thermodynamically stable form, which is often the most important aim of a polymorph screen. 

Mechanochemical co-crystallisation has also been exploited in the synthesis of readily compressible and thermodynamically stable forms of the API paracetamol (Figure 8.8(b)). While tablet formation using the thermodynamically stable polymorph of paracetamol is difficult, the metastable orthorhombic polymorph yields tablets much more readily due to its layered crystal structure. Consequently, it was expected that co-crystals of paracetamol with a similar layered structure would also be readily compressible. Screening by LAG revealed four co-crystals of paracetamol with improved ability to compress into tablets. Structural characterisation and Density Functional Theory (DFT) calculations revealed that enhanced compressibility was related to the formation of a sheet-like structure reminiscent of the second polymorph of paracetamol (Figure 8.8(c)-(e)). ... 

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