Spherical crystallization technique as a method to manipulate the particle shape and habit of pharmaceutical crystals
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Micromeritic properties of drug substance influence many of the powder properties important for downstream processing.  Formulation techniques such as tabletting by direct compression are setting high demands on the flowability and compressibility of the drug substance.  Increasing the particle size usually improves the flowability and compressibility of the particles. However, needle and plate shape particles tend to have poor flowability and very fine particles do not compress easily.  These micromeritic properties of the bulk powders are often determined by the selected polymorph.

Kawashima has in a number of publications described controlled agglomeration of crystals as a means of size enlargement during the crystallization step.  In 1984 Kawashima [1] used the spherical crystallization technique for size enlargement of pharmaceutical crystals.  By spherical crystallization agglomerated particles are created in the final recrystallization step of the synthesis with sizes ranging from 300 to 500 nm [2].

Figure 1.  Top image shows unprocessed particles and the bottom image shows agglomerates prepared by spherical crystallization.

Crystallics uses the spherical crystallization technique in its portfolio of methods to manipulate the particle shape and habit of pharmaceutical crystals.  The principle of spherical crystallization is based upon anti-solvent crystallization [3].  A saturated solution of the Active Pharmaceutical Ingredient (API) is poured into an anti-solvent.  Solvent and anti-solvent should therefore be miscible.  To promote agglomeration a third solvent is added in small amounts.  This “bridging liquid” should be not miscible with the anti-solvent and preferably should wet the precipitated crystals.  The challenge in developing a spherical crystallization process is in the selection of the solvents and, in particular, the “bridging liquid” as well as in determining the process parameters such as stirring rate, temperature and agitation.

As the selection of the solvents is solely dependent on the solubility profile of the API an extensive solubility determination is the start of any spherical crystallization process development project.  The solvent proportions need to be determined by constructing ternary phase diagrams.  The use of parallel crystallization equipment such as Crystal16™ and Crystalline™ crystallization reactors allows for the rapid evaluation of parameters such as mode and intensity of agitation, temperature and aging time.

A spherical crystallization process is a relative simple process for particle engineering and has been used over the last 25 years to improve bulk powder and tabletting properties of drug substances [2].  In addition, improvements in solubility and dissolution rate are also achievable [4].  A spherical crystallization process may be implemented as the final re-crystallization step in the synthetic process.

[1]         Y. Kawashima, Development of spherical crystallization techniques and its application to pharmaceutical systems, Arch. Pharm. Res. 7 (1984) 145–151.
[2]         Y. Kawashima, F. Cui, H. Takeuchi, T. Niwa, T. Hino, K. Kiuchi, Improvements in flowability and compressibility of pharmaceutical crystals for direct tabletting by spherical crystallization with a two-solvent system, Powder Technol. 78 (1994) 151–157. doi:10.1016/0032-5910(93)02772-3.
[3]         R. Parida, Evaluation parameters for spherical agglomerates formed by spherical crystallisation technique, Int. J. Pharma Bio Sci. 1 (2010).
[4]         Martino, Bartheleny, Pina, Improved dissolution behavior of fenbufen by spherical crystallization, Drug Dev. Ind. Pharm. 25 (1999) 1073–1081.