Solid state compatibility studies with tablet excipients using non thermal methods
Introduction
Pharmaceutical quality by design (QbD) is a systematic, scientifically based, holistic and proactive approach to pharmaceutical development [1], where selection of excipients following compatibility investigation is the first step towards the final pharmaceutical formulation. However, no general well defined principles for testing and selecting suitable excipients exist. This despite the fact that unfavourable combinations of drugs and excipients may alter both the stability and the bioavailability of the drug in the formulation [2], [3]. Consequently, a thorough drug-excipient compatibility study is a very important part of QbD and in general for the development of a stable pharmaceutical formulation [1], [3].
The collection of real-time stability and compatibility data is time-consuming and expensive, so obtaining rapid and reliable information about possible drug–excipient interactions is highly desirable. Differential scanning calorimetry (DSC) is the most commonly used method for assessing incompatibility between formulation components and the drug described in the literature, as it is fast, versatile and requires little sample [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. However, thermal techniques lead to complex data interpretation that may be misleading. Moreover, interactions observed at high temperatures during DSC experiments may not be relevant at normal storage temperatures [3], [8], [12], [13], [16]. In addition, the observation of solid–solid interactions may indicate other things than incompatibility [12], [16]. As water plays an essential role for interactions, DSC experiments should include humidity control [4], [17] which is not usually the case. If an incompatibility is observed by DSC, additional confirmatory experiments are often required [6], [9], [10], [11], [15], [17], [18], [19]. Therefore evaluating the compatibility directly by the methods normally used in the confirmatory experiments could be more relevant and beneficial from both an economical and time perspective.
Isothermal stress testing (IST) is a frequently used method in compatibility evaluations and involves storage of the drug-excipient blends with or without moisture at elevated temperature and subsequent investigation or determination of the drug content by a suitable method [2]. The methods used to detect incompatibility following IST include HPLC [2], [5], [8], [13], XRPD [7], [11], [14], [18], [19], FT-IR [6], [9], [10], [14], [19], [20], MS [15] and microcalorimetry [18].
Fourier Transform infrared spectroscopy (FT-IR) is a simple technique for the detection of changes within excipient-drug mixtures. Disappearance of an absorption peak or reduction of the peak intensity combined with the appearance of new peaks give a clear evidence for interactions between the excipient and the drug investigated. As a first approach, changes are unwanted and excipients interacting with the drug should be avoided if possible in the final formulation. Deeper insight into the mechanism of interaction can be obtained by the use of FT-IR, as the method allows assignment of the peaks and thereby provides valuable information about possible chemical changes. Compared to the other analytical methods used in compatibility studies, FT-IR has some clear advantages including: (i) it is non-disruptive, as no preparation of the samples is needed, (ii) recording does not influence the result, and (iii) changes in crystal structure may be detected, i.e. desalting, hydrate formation or polymorphic changes.
The different methods for compatibility testing can only provide a rough indication for the selection/deselection of excipients, as the composition of the final formulation may be different from the one tested in the compatibility study and because the reaction kinetics may be different under the stress conditions used [21]. The purpose of the current study is therefore to evaluate an accelerated stress method and to compare it to a traditional long-term method–3 days versus 12 weeks by the use of FT-IR and HPLC, respectively.
Section snippets
Materials
The chemical structures of the two active pharmaceutical ingredients are shown in Fig. 1, denoted Lu AA44608 (where the HBr salt was used) and Lu AA47070. Both compounds were produced by H.Lundbeck A/S (Valby, Denmark). Calcium hydrogen phosphate anhydrate was purchased from Budenheim (Budenheim am Rhein, Germany), talc from Scheruhn Industrie-Mineralen (Hof, Germany), maize starch from Roquette (Le Strem, France), lactose from DMV International (Veghel, The Netherlands), crospovidon (Kollidon
Characterisation of the compounds
Lu AA44608 has a single pKa-value, determined to be 4.8 and a log P (and log D7.4) of 3.1. The solubility of the free base in water (pH 8.0) and in buffer (pH 7.4) is approximately 1 μg/ml. The hydrogen bromide salt transforms into the free base in aqueous solution. The compound melts with Tons around 184 °C, and is not hygroscopic absorbing less than 0.1% water at 95% relative humidity at ambient temperature. The compound in solution is very sensitive to light but stable when exposed to acidic
Conclusions
This study has demonstrated that IST/FT -IR can detect potential compatibility problems between an API and pharmaceutical excipients after only 3 days of storage. The method provided some insight into the reaction mechanisms by allowing the assignment of the bands in the spectra, which provides the preformulation and formulation scientists with information about which chemical groups to avoid in the excipients.
Acknowledgement
Kirsten Lech-Rasmussen is acknowledged for linguistic support.
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