Article pubs.acs.org/crystal
Comparison Study of Different Spherical Crystallization Methods of Ambroxol Hydrochloride Orsolya Gyulai,* Piroska Szabó-Révész, and Zoltán Aigner University of Szeged, Department of Pharmaceutical Technology and Regulatory Affairs, 6, Eötvös St., 6720 Szeged, Hungary ABSTRACT: Production of spherical crystals with an appropriate particle size is an important objective for active agents dedicated to direct tablet making (Diao et al. Nat. Mater. 2011, 10, 867−871; Tahara, K. et al. Cryst. Growth Des. 2015, 15, 5149−5156). The material chosen for our experiments, ambroxol hydrochloride, is such a solid compound. The optimal habit for the crystals of direct compressible active agents and additives includes sphericity, proper mean particle size, and appropriate surface. The main objective of the present work is to compare typical and nontypical spherical crystallization methods and to investigate their applicability for ambroxol hydrochloride. The particles were investigated by light microscopy, coupled with an image analyzator program, scanning electron microscopy, powder X-ray diffractometry and differential scanning calorimetry in order to obtain information about particle morphology, mean particle size, aspect ratio, roundness and potential polymorphic transitions. Powder rheology properties were also investigated. The typical crystallization method of quasiemulsion solvent diffusion was suitable for increasing mean particle size, but large-size spherical crystals did not form. Nontypical spherical crystallization methods (spherical agglomeration and the method of cooling with an alternating temperature profile) caused an increase in mean particle size and an improvement in aspect ratio and roundness. Powder rheology parameters of the spherical agglomeration products improved, too.
1. INTRODUCTION Generally, crystallization is the last step of the production of solid form active pharmaceutical ingredients (APIs) and additives. The process of crystallization is suitable not only for purification, but also for achieving a proper crystal size and morphology.1 Particle surface, size, and distribution influence many properties of solid materials and are valuable indicators of quality. The size and shape of the particles influence flow and compaction properties.2 As particle size is a well-known determinant of dissolution with smaller particles dissolving faster, methods of particle size reduction have been in the focus of pharmaceutical technological research in the past decade, especially in the case of materials with low solubility.3 However, larger and spherical-like particles are typically characterized by a better flowability compared to smaller particles with a high aspect ratio; thus the former are more suitable for direct compression.4,5 A slow crystallization process with low supersaturation results in larger crystals.6 Particle size enlargement of several drug materials can be accomplished by spherical crystallization, for example, magnesium aspartate, acetylsalicylic acid,7−9 paracetamol,10 and ibuprofen.11 Large and goodflowing particles are also better for encapsulation.12 The advantage of applying direct compression for a solid and crystalline API is the avoidance of granulation, which is a time and money consuming process from an industrial point of view. It is also advantageous when the API or the excipients are thermolabile or moisture-sensitive. For direct compression © XXXX American Chemical Society
tableting, it is optimal to obtain large-size spherical crystals in order to improve the flowability, compactibility, and compressibility of the API. Producing spherical crystals suitable for direct tableting allows the amount of additives to be reduced; thus tablet size can be decreased, facilitating swallowing.13 It is known that modifying the solvents and the conditions applied for the crystallization process affects particle size and morphology.14,15 Two main types of spherical crystallization procedures are distinguished: typical and nontypical ones. The typical spherical crystallization usually includes three solvents, namely, a good solvent, an antisolvent, and a bridging liquid which is miscible with the other two plus wets the active agent.16 Usually an emulsifier is also used for this technique to stabilize the emulsion droplets and to maintain a homogeneous droplet size.17 The most well-known typical spherical crystallization method is the quasi-emulsion solvent diffusion technique.18−21 In the case of nontypical spherical crystallization methods such as spherical agglomeration, which is an antisolvent technique,22−24 or programmed cooling crystallization25−29 (or these two combined30,31) only one solvent phase is present. The main aim for using an alternating temperature profile is to standardize particle size distribution; thus, when the system is heated up, smaller particles dissolve while the larger particles Received: June 2, 2017 Revised: August 28, 2017 Published: August 30, 2017 A
DOI: 10.1021/acs.cgd.7b00764 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
2.2.2. Crystallization Utilizing Typical Methods. 2.2.2.1. QuasiEmulsion Solvent Diffusion Technique (QESD). As good solvents W/ MeOH (volume ratio of 1:3) and W/EtOH (volume ratios of 3:1 and 1:1) mixtures were used, since AMB-HCl was found to have the two highest solubility values in these solvents. The bridging liquid was MeOH and EtOH, respectively, since these solvents are miscible with both the solvent and the antisolvent, and they wet the active agent well. Ethyl acetate, isopropyl acetate, n-pentane, n-hexane, n-heptane, and n-dodecane were used as antisolvents. A solvent/antisolvent ratio of 1:5 was applied based on literature data.41 The effects of different types and amounts of emulsifiers were also investigated using mixtures of Span 80/Tween 20 and Span 80/Span 20, setting a HLB (hydrophilic−lipophilic balance42) value that contributes to the most stable emulsion and gives the highest yield.
decrease in size and their roundness improves. Then, during the solution’s cooling phase, new particles crystallize onto the surface of these still larger but rounder particles. Seeding is a very important moment in this case because the main aim of the process is to keep the number of the particles constant by the enlargement of the seeding particles.32 Besides crystal morphology, polymorphism is another critically important parameter which can be modified by using different types of solvents and solvent mixtures. In the field of crystallization, the exact polymorphic forms always have to be identified and described, because different forms can have different physical and physicochemical properties such as solubility.33 Ambroxol hydrochloride has got one known polymorphic form which has got the same powder X-ray diffraction (PXRD) pattern as ours.34 Ambroxol hydrochloride (AMB-HCl) was chosen for our experiments, because scarce research has been reported on the crystallization of this API, although it is known that direct compression is the readily accepted method for the preparation of ambroxol tablets.35,36 This API usually crystallizes in small particles (
