complicating the subsequent design of a crystallisation process . Another important factor to evaluate is whether solvent molecules have been incorporated into the crystal lattice , leading to solvates or , in the case of water , hydrates . Solvates and hydrates can be formed with the API itself or with its salts and co-crystals . While organic solvates are rarely selected for further development due to toxicity and physical stability considerations , knowing which solvents lead to solvate formation is crucial when deciding which solvents to avoid in the final crystallisation step of a synthesis process or in formulation development . In addition , the desolvation of solvates can sometimes serve as a convenient route to generating the most stable solid form . 4 Crystalline hydrates do not present a toxicity risk since their extra component is water , but the development of a hydrate requires an understanding of its physical stability relative to key anhydrous forms at various water activities ( i . e . relative humidities ) so that it does not dehydrate into an undesired form upon storage . The aqueous solubility of hydrated forms is also important for understanding bioavailability since high-order hydrates ( if they exist ) will be the forms into which APIs ultimately transform in the water-rich environment of the human body . Hygroscopic solids , whether hydrates or anhydrous forms , often have high bioavailabilities . Thus , they do not necessarily have to be avoided if the water uptake only occurs at extremely high relative humidities , but , like hydrates , they do have limited options for formulation and storage .
Special conditions
To produce a specific state of hydration or to avoid deliquescence , special drying and packaging conditions are often needed . A hydrate cannot be so extensively dried that its water molecules are removed since it might become amorphous or undergo a solid-form transformation in the process . Similarly , drying a deliquescent polymorph does not necessarily cause it to convert back into its original form . Strict humidity controls could be necessary in the manufacturing plant and robust blister packaging might be required to extend the shelf life of the drug product . Such steps can add significant costs to bringing such a drug to market , but they can still be worthwhile if the benefits of a particular hydrated or hygroscopic form outweigh the drawbacks . After evaluating various physico-chemical properties , such as thermodynamic stability , chemical stability , chemical purity , hygroscopicity , solubility , dissolution rate , ease of preparation and processability , as well as economic factors , such as the costs of producing a multi-component versus a single-component system and the volume efficiencies and toxicities of non-solvate-forming solvents , the solid form with the best combination of properties is selected and , often , patented ( Figure 1 ). At this point , analytical method development , formulation strategies and process optimisation generally proceed in parallel . Solid-form choice can dictate formulation options . The choice of
Figure 1 - Solid-state development : An integrated approach
36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981