Drug Discovery & Pharmaceuticals
A Quick and Easy Evaporative Crystallisation Screen for Drug Candidate Polymorphism
Alison Wake, Genevac Ltd - part of SP Scientifi c
During drug development initial identifi cation of a new Active Pharmaceutical Ingredient (API) usually yields an amorphous form of the compound. However, compounds which are crystalline in nature often adopt a number of crystalline forms or polymorphs. The different physical characteristics of these polymorphs can impact on the manufacturing process as well as the effi cacy of the drug and initial screening undertaken on an amorphous form may be misleading, as crystallisation may change properties such as dissolution rate and biological activity. Polymorph screening is therefore an important stage in the drug development process, the aim being to identify the different crystalline structures that a drug may adopt. Information gained is used to optimise the physical properties of the drug compound, to ensure effi cacy, and provide formulation and manufacturing consistency.
In this study Medicinal Chemists from one of our pharmaceutical customers in Japan evaluated the Exalt Controlled Crystallisation system from Genevac as a method of polymorph screening in their drug discovery programme. To evaluate the process a widely available compound, Piroxicam, which is known to form three different polymorphs [1] was chosen.
Method
Exalt is a method for evaporative crystallisation developed by Genevac which enables solutions of API in a wide range of solvents to be evaporated at the same time, and all at the same slow rate, producing crystals. Exalt uses a special holder for vials which allows a selection of baffl es to be placed on top of each vial to slow the evaporation rate of volatile solvents (Figure 1). The size and number of baffl es are selected to be most restrictive for the most volatile solvents, and least restrictive to the less volatile solvents. The holder is then placed in a Genevac HT series evaporator which cycles at atmosphere and at a slightly reduced pressure for the duration of the evaporation process.
Table 1. Solvents screened, Exalt confi guration, and physical appearance of product after 72 hours evaporation.
No. 1 Solvent Dichloromethane
2 Tertiary Butyl Methyl Ether 3 4 5 6 7 8 9
Acetone
Methyl Acetate Chloroform
Tetrahydrofuran Hexane
Methanol
10 11 12 13 14 15 16 17 18 20 21
Cyclo Hexane Ethyl Acetate
Methyl Ethyl Ketone Acetonitrile
1,2-Dimethoxy Ethane Ethanol
Isopropyl Acetate Heptane
Isopropyl Alcohol Toluene
1,4-Dioxane Benzene
Volume
3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 1ml 2ml 1ml 1ml
Tower
#21 #17 #16 #16 #14 #12 #15 #10 #9
#10 #10 #4 #1
None None None None None None None
Physical Appearance after 72hr
Powder Solid
Crystal Solid Solid
Solution (1ml) Solution (0.5ml) Needle crystal Powder
Solution (0.5ml) and needle crystal Solution (0.5ml) Solution (0.5ml) Solution (0.5ml) Solid
Candy
Powder Powder
Solution (0.5ml) Solid
Cubic crystal
Figure 1. Exalt toolkit.
Solutions of Piroxicam were prepared in a range of solvents (see Table 1) to yield a solution of 2mg/ml. 3ml of each solution was placed into a vial and capped with a tower, containing baffl es, as recommended by Genevac [2]. The lower volatility of six solvents meant that no tower was required. In addition, to ensure complete evaporation by the end of the run, three of these solvents also required a reduction in initial volume (concentration of these solutions was corrected to yield 6mg per vial). The complete holders were then placed in to a Genevac HT-4X evaporator, running the Exalt programme, for 72 hours.
Results
Table 1 lists the 20 solvents screened, the tower confi guration, and physical appearance after 72hr evaporation. Seven vials had not fully evaporated and required further evaporation in the HT4X. Subsequently 19 out of the 20 solutions yielded a crystalline solid suitable for X-Ray Diffraction (XRD) analysis. Analysis of XRD results (Figure 2) indicates that the Exalt screening method was able to identify polymorphs of types I, II and III (Table 2). For three solvents results were inconclusive and whilst these were thought to be solvates further investigation would be required to confi rm this.
Figure 2. XRD results of crystals formed using Exalt controlled crystallisation
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