CRYSTAL GROWTH & DESIGN
Toward an Understanding of the Factors Influencing Anhydrate-to-Hydrate Transformation Kinetics in Aqueous Environments
2008 VOL. 8, NO. 8 2684–2693
Håkan Wikstro¨m,† Jukka Rantanen,‡,§ Alan D. Gift,| and Lynne S. Taylor*,† Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue UniVersity, West Lafayette, Indiana 47907, Viikki Drug DiscoVery Technology Center (DDTC), Pharmaceutical Technology DiVision, UniVersity of Helsinki, Finland, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, UniVersity of Copenhagen, Denmark, and Department of Chemistry, UniVersity of Indiana South Bend, South Bend, Indiana 46634 ReceiVed July 7, 2007; ReVised Manuscript ReceiVed March 17, 2008
ABSTRACT: Approximately one-third of all drugs can form hydrates, and therefore an in-depth understanding of the factors affecting anhydrate-to-hydrate transformation kinetics in a variety of environments is of interest. In this work, real-time analytical methods, in the form of Raman spectroscopy and optical microscopy, were used to establish representative transformation profiles and growth kinetics for hydrate formation of several drug substances. By comparing and contrasting the behavior of these different hydrates in terms of their specific properties such as solubility, dissolution rate, and growth rate of hydrate phase, and the influence of external factors such as seeding and agitation conditions, an increased understanding of hydrate formation has been achieved. The overall transformation rate from anhydrous to hydrate form was found to be not only a function of compound-specific properties, but was also strongly affected by surface properties and external factors such as the presence of seeds and the degree of shear forces. Introduction Solvent-mediated transformations (SMTs) are phase transformations between different solid state forms that can occur following exposure to bulk solvent.1,2 SMTs are important for pharmaceutical systems because they may alter the performance of the final dosage form through impacting properties such as solubility, dissolution rate, hygroscopicity, stability, and ultimately bioavailability. It can be anticipated that compounds that exist as both anhydrate and hydrate forms might be susceptible to SMTs during unit operations such as aqueous crystallization, wet granulation, or even aqueous film coating. Approximately one-third of all drugs can form hydrates, and although the hydrate may be the thermodynamically stable form,3 for various reasons, the anhydrate may be the bulk drug substance which is used for secondary manufacturing. As mentioned previously, conversion of the anhydrate to the hydrate during processing may be detrimental to product quality, not only because of solubility changes, but also because a SMT during a unit operation is essentially an uncontrolled recrystallization that will lead to changes in drug morphology and other particulate properties. Hence, it is of interest to understand the kinetics of hydrate formation in the types of aqueous environments relevant to pharmaceutical processing. Hydrate formation through a solvent-mediated transformation has been widely discussed in the literature.4–7 The transformation can be divided into three stages. First there is a dissolution stage, where the anhydrous drug is dissolved in the aqueous solvent. Second, nuclei are formed once the solution is supersaturated with respect to the hydrate phase. Lastly, there is a growth stage, when the hydrate drug grows from the nuclei to form larger crystals. The growth is maintained as long as the solution is supersaturated with respect to the hydrate phase. Various * To whom correspondence should be addressed. E-mail: ltaylor@ pharmacy.purdue.edu. † Purdue University. ‡ University of Helsinki. § University of Copenhagen. | University of Indiana South Bend.
attempts have been made to model SMTs, and of these the Cardew and Davey model is one of the most referenced.2 In this model, the authors used dissolution and growth rates of the metastable form and the stable form, respectively, and related the transformation to the degree of supersaturation. The Cardew and Davey model was later modified using the populationbalance approach that included a nucleation term by Thompson and Dixon.8 Aqueous wet granulation is currently the most widely used technique to improve homogeneity, flowability, and compactability of formulations in the production of pharmaceutical solid dosage forms.9 While the phenomenon of hydrate formation during wet granulation has been documented,6,10 the factors affecting the kinetics of the transformation are not wellunderstood, and important substance and process variables remain to be elucidated. Furthermore, analytical difficulties often arise due to the need to sample and measure remotely leading to uncertainties regarding the exact kinetic profile. The goal of this work was to investigate the transformation kinetics of several model hydrate formers in two different aqueous environments, namely, a low shear, water-rich slurry system and a higher shear, lower water content, granulation environment. Real-time analytical methods in the form of in situ Raman spectroscopy were utilized to obtain representative transformation profiles. The behavior of the different hydrates was then compared and contrasted in terms of compoundspecific properties such as hydrate solubility, anhydrate and hydrate dissolution rates, and hydrate growth rate, as well as assessing the influence of external factors such as seeding and agitation conditions. Materials and Methods Materials. Five different model compounds were used for this study and their chemical structures are shown in Table 1. The materials evaluated were nitrofurantoin anhydrous (NF, Sigma-Aldrich, Inc., St. Louis, MO, USA), theophylline anhydrous (TP, Ruger Chemical Co., Inc., Irvington, NJ, USA), caffeine anhydrous (CAF, Knoll AG, Ludwigshafen, Germany), sulfaguanidine monohydrate (SFG, Sigma-
10.1021/cg070629e CCC: $40.75 2008 American Chemical Society Published on Web 06/19/2008
Anhydrate-to-Hydrate Transformation Kinetics
Crystal Growth & Design, Vol. 8, No. 8, 2008 2685
Table 1. List of Model Compounds and Some Compound-Specific Propertiesa
a
CSD, Cambridge Structural Database. Table 2. Summary of Calibration Models Used for Quantitation of the Transformation Kineticsa material
caffeine carbamazepine nitrofurantoin sulfaguanidine theophylline
calibration model
νanhyd/νhyd [cm-1]
bivariate PLS univariate bivariate bivariate
1699/1655
range [cm-1] 1530-1650
1610 (1614 ref) 819/828 1707/1686
pretreatment SNV/Ctr
# of PCs 2
R2 Y 0.981 0.993 0.941 0.986 0.984
Q2 0.993
RMSEC/P 5.6/5.4 2.9/3.4 5.0/4.4 5.2/6.2 5.3/10.2
a νhyd, characteristic vibration for hydrate; PC, principal component; R2Y, correlation coefficient; Q2, cross-validation coefficient; RMSEC/P, root mean square error of calibration/prediction; PLS, partial least squares; Ref, reference vibration; SNV, standard normal variate transformation; Ctr, mean centering.
Aldrich, Inc., St. Louis, MO, USA), and carbamazepine anhydrous (CBZ, Hawkins, Inc., Minneapolis, MN, USA). All starting materials were dried in an oven according to their dehydration temperature, which was determined using thermogravimetric analysis as described below, and equilibrated in a desiccator (
