Improving solubility with promiscuous multi-component drug crystals

Posted: 22 October 2015 |

The physicochemical properties of active pharmaceutical ingredients (APIs) are critical to the success of drug development. Most of the APIs in oral solid dosage forms are contained as drug crystals.

Improving solubility with promiscuous multi-component drug crystals

Drug crystals can be categorised as single and multiple component systems, the latter of which include salts, co-crystals and solvates. When the solvent is water, the drug solvate is referred to as a hydrate. Salts formation is defined as proton transfer from a drug molecule to a guest molecule and the guest molecule (i.e., a counter-ion) is bonded to the drug molecule (i.e., a drug) by one or several ionic bonds. In a co-crystal and a solvate, a guest molecule (a co-crystal co-former or a solvent) is bonded to the drug via inter-molecular interactions other than the ionic bond, such as with hydrogen bonds. Co-crystal co-formers are non-volatile molecules at ambient conditions. In most cases, the drug solvates of APIs are hydrates; however, they can be organic solvents.

Multi-component crystals are widely used to improve the physico-chemical properties of APIs, such as solubility, stability, powder compaction and bioavailability. When the drug possesses a dissociable group, salt formation is usually utilised. Recently, co-crystals have been intensively investigated for their ability to improve the solubility of undissociable drugs. Although organic solvates have received less attention compared with co-crystals, some have also been utilised as APIs, including indinavir sulphate ethanolate, efonidipine hydrochloride ethanolate, metildigoxin acetonate, ledipasvir acetonate, and dapagliflozin propylene glycolate hydrate. Moreover, some drugs tend to form several organic solvates, which are collectively referred to as ‘promiscuous solvate formers’. These promiscuous solvate formers offer new opportunities to improve the solubility of a drug; however, they could also be problematic from the viewpoint of manufacturability. In this review, several examples of promiscuous solvate formers are discussed.

Examples of promiscuous pseudo-polymorphs


Axitinib (axitinib, Pfizer) is a drug that targets vascular endothelial growth factor6. It is capable of forming five anhydrate polymorphs and 66 pseudo-polymorphs. In its crystal form, it has a large polymorph space7. During the later stage of the development of axitinib, a more stable low-energy polymorph emerged, indicating the need to intensively screen for polymorphs and pseudo-polymorphs. Several screening technologies were employed, such as fast evaporation, slow cooling of saturated solutions and slurry methods at different temperatures. These screening methods were effective at thoroughly finding the pseudo-polymorphs of axitinib.


The crystal structure of the host molecules in multi-component crystals is sometimes classable. Sulphathiazole is an antibacterial drug that is known to crystallise over 100 solvates and co-crystals, and shows five polymorphs8. Two types of crystal structures have been identified9, as determined by the assemblage between the guest molecule and sulphathiazole: a) clathrates, in which the host molecules have a channel, layer, or three-dimensional framework structure and the guest molecule fills the cavity; b) co-crystals, in which the guest molecule is an essential part of the hydrogen-bonded framework. Salt formation was observed in both cases.


The flexibility of a molecule is important when considering crystal structure classification. Methylene carbon chains make a molecule flexible, increase the number of structure classes, and make the structure classes more continuous. For example, furosemide (Lasix, Sanofi) forms four pseudo-polymorphs: tetrahydrofuran solvate (1:1), 1,4-dioxane solvate (1:1), N,N-dimethyl formamide solvate (1:1), and dimethyl sulphoxide solvate (1:1)10. These pseudo-polymorphs show four different conformations originating from the methylene carbon. Diverse solvents can be included in the crystal because of the flexibility of the molecule.


In contrast to flexible molecules, structurally rigid molecules show a lower number of conformations. However, even these molecules can include diverse solvents in spite of lesser flexibility, as is the case with olanzapine. Olanzapine (originally branded Zyprexa by Eli Lilly) forms pseudo polymorphs with diverse solvents11,12. Two hydrates (2 hydrate, 2.5 hydrate), a dichloromethane solvate (2:1), and a methanol (1:1) are found in the Cambridge structure database. Triple component pseudo polymorphs are also found: olanzapine-water-ethanol (2:2:1), olanzapine-water-butanol (1:1:1) and olanzapine-water-dimethyl sulphoxide (1:1:1). When comparing the crystal structures of these pseudo-polymorphs, the olanzapine molecule forms a mirror image pair in all crystals, and the solvent molecules are positioned between the pairs of olanzapine molecules. Most of the solvent molecules form four hydrogen bonds with the two pairs of olanzapine molecules. The tendency of olanzapine to form a mirror image pair is also observed in anhydrate crystals. It is likely that the pair of olanzapine molecules is the key factor for supramolecular building blocks. The building block would be capable of generating diverse crystal forms because of the adjustable space between the olanzapine molecules.


Some solvent molecules in pseudo-polymorphs are capable of being exchanged with different solvent molecules in the vapour phase. Pranlukast (Onon, Azlaire), a leukotriene receptor antagonist, forms eight pseudo-polymorphs with seven solvents, i.e., water, methanol, ethanol, 1-propanol, N,N-dimethyl formamide, dimethyl sulphoxide, and propylene glycol13. Their crystal structures are classified as a sheet-like and channel-like pattern. Pranlukast hemihydrate, N,N-dimethyl formamide solvate, dimethyl sulphoxide solvate and water-methanol solvate form the sheet-like pattern. The sheet-like pattern includes a solvent in the space between the sheet structures of pranlukast molecules. In contrast, pranlukast methanol solvate, ethanol solvate, and 1-propanol solvate form the channel-like pattern. Single crystal X-ray diffraction analysis revealed that the channel-like pattern only exists in the pseudo-polymorphs with alcohols. The pseudo-polymorphs of the channel-like pattern solvates can transform into a hydrate with the sheet-like pattern in a humidified environment. Solvent exchange can also occur from alcohols to water. However, it is not known whether or not the solvent exchange reaction is invertible.

Structural features of promiscuous pseudo-polymorphs

The existence of a space that can expand or contract to fit the solvents in the crystal structure appears to be important for the formation of pseudo-polymorphs with diverse solvents, regardless of whether the space is intramolecular or between molecular complexes.

Advantage of pseudo-polymorphs

The use of pseudo-polymorphs can promote effective drug development. Pranlukast is a poorly soluble compound of the biopharmaceutical classification system class IV. In previous studies, pranlukast was formulated as a nanosuspension14 and high-pressure homogenised formulation15 to improve the dissolution behaviour and oral absorption. Recently, we found that the dissolution behaviour of pranlukast can be improved by using an ethanol solvate13 (Figure 1; page 00). In addition, desorption of a solvent from a pseudo-polymorph can be a method for producing a specific polymorph. For example, the four pseudo-polymorphs of furosemide transform to different anhydrate crystals by solvent desorption. Furosemide-tetrahydrofuran (1:1) transforms to anhydrate form III, whereas furosemide-dimethyl sulphoxide (1:1) transforms to anhydrate form I10. In general, severe control of temperature and concentration is necessary to generate a specific polymorph by recrystallisation. Solvent desorption of a pseudo-polymorph may provide a new approach for generating specific polymorphs.


In the future, it should become standard practice to study pseudo-polymorphs so as to improve the physical property of drugs in development. Pseudo-polymorph formation does not require chemical structure modification and conversion to a pseudo-polymorph can improve the dissolution behaviour of poorly soluble compounds. The use of pseudo-polymorphs can provide an effective method to generate specific polymorphs. These cases indicate that pseudo-polymorphs can be a solution to the problems often encountered in drug development. However, there is some difficulty in manufacturing pseudo-polymorphs. When a pseudo-polymorph is being applied as an API, it is important to pay sufficient attention to the desolvation and transformation processes in drug development.


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Masataka Ito is Assistant of Pharmaceutics in the Faculty of Pharmaceutical Science, Toho University, Japan. His research focuses on the physical characterisation of pharmaceutical solid and drug formulation design. He conducted research at TOWA Pharmaceutical Co.. Ltd. during 2012 until 2015. He received his BS in 2012 at Toho University. Contact Masataka at: [email protected]

Kiyohiko (Kiyo) Sugano is Associate Professor of Toho University. He has over 18 years of experience working within the pharmaceutical industries in Japan and the UK (Chugai, Pfizer and Asahi Kasei Pharma). He received his Bachelors and Masters degrees in Chemistry from Waseda University. He received his PhD degree in Pharmaceutical Sciences from Toho University.

Dr. Katsuhide Terada is Professor of Pharmaceutics in the Faculty of Pharmaceutical Sciences, Toho University in Japan. His research interests include the physical characterisation of pharmaceutical solids and the quality control in the manufacturing process using many kinds of analytical methods. He is the author and or co-author of more than 210 research papers, 50 reviews and 50 book chapters. He is an active member of several professional organisations, president of Japan chapter of PDA, former president of Japanese Society of Pharmaceutical Machinery and Engineering (JSPME). He received his BS in 1975 and MS in 1977 at Chiba University and received a PhD in 1983 at the University of Tokyo.

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