Article pubs.acs.org/molecularpharmaceutics
Quantification, Mechanism, and Mitigation of Active Ingredient Phase Transformation in Tablets Naveen K. Thakral,† Vishard Ragoonanan,† and Raj Suryanarayanan* *
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-177 WDH, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States S Supporting Information *
ABSTRACT: Model tablet formulations containing thiamine hydrochloride [as a nonstoichiometric hydrate (NSH)] and dicalcium phosphate dihydrate (DCPD) were prepared. In intact tablets, the water released by dehydration of DCPD mediated the transition of NSH to thiamine hydrochloride hemihydrate (HH). The use of an X-ray microdiffractometer with an area detector enabled us to rapidly and simultaneously monitor both the phase transformations. The spatial information, gained by monitoring the tablet from the surface to the core (depth profiling), revealed that both DCPD dehydration and HH formation progressed from the surface to the tablet core as a function of storage time. Film coating of the tablets with ethyl cellulose caused a decrease in both the reaction rates. There was a pronounced lag time, but once initiated, the transformations occurred simultaneously throughout the tablet. Thus the difference in the phase transformation behavior between the uncoated and the coated tablets could not have been discerned without the depth profiling. Incorporation of hydrophilic colloidal silica as a formulation component further slowed down the transformations. By acting as a water scavenger it maintained a very “dry” environment in the tablet matrix. Finally, by coating the NSH particles with hydrophobic colloidal silica, the formation of HH was further substantially decelerated. The microdiffractometric technique not only enabled direct analyses of tablets but also provided the critical spatial information. This helped in the selection of excipients with appropriate functionality to prevent the in situ phase transformations. KEYWORDS: thiamine hydrochloride, dicalcium phosphate dihydrate, two-dimensional X-ray diffractometry, colloidal silica, depth profiling, tablet
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istration.6 The market recall of ritonavir capsules, due to the formation of the more stable polymorph, has been widely known and extensively studied.7,8 More recently, 60 million tablets of Avalide, a combination of two antihypertensive drugs, hydrochlorthiazide and irbesartan, were recalled. This was brought about by the presence of the less soluble polymorph (form B) of irbesartan, which may result in slower dissolution.2,9 Most of the attention in the literature has focused on the API. It is important to recognize that alterations in the physical form of an excipient, during product manufacture or storage, can also affect product performance. Dicalcium phosphate dihydrate (DCPD) is widely used as a tablet diluent. In a model formulation containing amorphous sucrose and DCPD, the water released by the dehydration of DCPD caused the plasticization of sucrose and its subsequent crystallization.10 Water sorption by povidone, added as a binder, caused its transition from a glassy to rubbery state resulting in tablet
INTRODUCTION The importance of chemical stability of the active pharmaceutical ingredient (API) in a dosage form has long been recognized. This is reflected in the assay for the API specified in the monograph of every formulation in the United State Pharmacopoeia.1 The prescribed assay methods are designed to evaluate the chemical integrity of the API. With recent advances in analytical instrumentation, this can be accomplished with a great deal of precision and accuracy. In solid dosage forms, the physical form of the API can also influence the final product performance. The term physical form encompasses the polymorphic form, the state of solvation, and the degree of crystallinity of the analyte. Several cases of in situ phase transformations, profoundly affecting product performance, have been comprehensively summarized by Lee et al.2 Storage of anhydrous carbamazepine tablets under “accelerated” conditions (RT or 40 °C; 97% RH) for just one week caused a dramatic alteration in dissolution behavior, and the stored tablets failed to meet the USP dissolution specifications.3 The in situ formation of CBZ dihydrate was believed to be responsible for this observation.4,5 Tablets that failed the USP dissolution specifications also exhibited a pronounced decrease in bioavailability following oral admin© 2013 American Chemical Society
Received: Revised: Accepted: Published: 3128
March 25, 2013 June 12, 2013 June 19, 2013 July 22, 2013 dx.doi.org/10.1021/mp400180n | Mol. Pharmaceutics 2013, 10, 3128−3136
Molecular Pharmaceutics
Article
model API, exists as a nonstoichiometric hydrate (NSH) with water content ranging between 0 and ∼1 molecule of water per molecule of thiamine hydrochloride. In the presence of water (liquid or vapor), it can transform to thiamine hydrochloride hemihydrate (HH).24 HH can undergo solution-mediated transformation back to an isomorphic desolvate of NSH.24 Preliminary studies revealed that the water released by the dehydration of DCPD facilitated the NSH → HH transition. However, the phase transformation mechanism in tablets is not known. Therefore our objectives were to (i) simultaneously study the kinetics of two reactions, DCPD → DCPA, and NSH → HH; (ii) understand the propagation of these reactions by monitoring, in increments of 50 μm, from the tablet surface to the core (spatial resolution); and (iii) develop strategies to prevent the phase transformation. All our investigations were conducted in intact and split tablets.
densification, increase in tensile strength, and decrease in dissolution rate.11 The influence of excipients on solid dosage form stability has been comprehensively summarized by Narang et al.12 If we wish to prevent in situ phase transformations, it is important to understand the mechanism of instability. In systems exhibiting physical instability, the most relevant information will be obtained by directly analyzing the dosage form. As mentioned earlier, conventional analytical techniques are designed to ensure the chemical stability of the API and require the analyte to be in solution prior to analysis. By dissolution of the solute, pertinent information about the physical form of the analyte is lost. In recent years, several approaches have been developed to analyze dosage forms directly. Powder X-ray diffractometry, spectroscopic techniques (IR, Raman, solid-state NMR), and calorimetry have enabled phase characterization in solid dosage forms (tablets).13−15 However, most of these techniques typically provide “average” phase information in the sample. In order to obtain mechanistic insights into phase transformations in tablets, an ideal analytical technique should be able to (i) simultaneously quantify the reactant and product phases and (ii) provide the above information with spatial resolution. The latter reveals where the reaction is initiated and the distribution (from the surface to core) of both the reactant and product phases. Terahertz pulsed imaging has been used to identify multiple polymorphs in intact tablets.16 This versatile technique can also characterize other tablet attributes including the film coating thickness. But the complex nature of pharmaceutical tablets can complicate data analyses.16 Raman microscopic mapping has been used to detect polymorphic impurity even in tablets containing a low concentration of API.17 But because of the weak scattering, information is predominantly obtained only from the tablet surface.18 Likewise, grazing incidence X-ray diffractometry was used to depth-profile phase transformations during tablet compaction and dissolution, but predominantly in the surface region of tablets.19,20 In this research, we used an X-ray microdiffractometer with an area detector which provides a two-dimensional image and is therefore referred to as two-dimensional diffraction.21 Data collection time with this setup is usually several orders of magnitude shorter than with conventional instruments. Since a substantial part of the diffraction ring is collected, errors due to preferred orientation can be significantly reduced. The rapid data collection, the enhanced signal intensity (two-dimensional image), and the potential reduction in errors due to preferred orientation make two-dimensional diffraction particularly wellsuited for quantitative analyses of complex systems containing multiple analytes. Our overall goal was to evaluate, in intact tablets, the effect of water released by an excipient on the physical stability of an API. We simultaneously studied two processes: excipient dehydration and API phase transformation. Dicalcium phosphate dihydrate (DCPD), a widely used diluent in tablets, was the model excipient. When stored under pharmaceutically relevant conditions, dehydration of DCPD resulted in the release of lattice water and the formation of dicalcium phosphate anhydrate (DCPA).22,23 The rate of DCPD dehydration is highly dependent on the relative humidity of storage. For example, at 60 °C/0% RH, 10% of DCPD dehydrated in ∼40 h, while at 60 °C/70% RH, the same extent of dehydration required
