Purpose: Preparation of pharmaceutical molecular complexes is investigated to improve the physiochemical properties such as stability and solubility. Especially, the cocrystal engineering has been reported to improve the properties of an active pharmaceutical ingredient (API). When the cocrystal of an API is used for a solid dosage formulation, additional pretreatment is required for the cocrystallization. Moreover, crystalline transition of the cocrystal may occur during the process for manufacturing, which leads unexpected property of products such as lower solubility. The other method for the preparation of cocrystal is to form cocrystals during the duration of manufacturing processes such as mixing, granulation, drying and tableting. In other words, the methodology is a continuous manufacture of pharmaceutical products of cocrystal API. In this method, therefore, it is strongly required to monitor the crystalline structure of the API and control the processes. The process control based on process analytical technology (PAT) and quality-by-design (QbD) are pivotal concepts for the pharmaceutical industry to produce consistent quantities of high-quality products.
In this study, granules of cocrystal API were prepared by one-step method without the preprocess of cocrystal formation. The one-step method was performed to prepare cocrystal between indomethacin and saccharin with high shear granulation process. The effect of starting polymorphism of indomethacin on the cocrystal formation was investigated using Raman spectroscopy. The dissolution property of granules was also analyzed.
Methods: As the additives, α-lactose monohydrate (LAM, Pharmatose 200M), microcrystalline cellulose (MCC, Ceolus PH-102), hydroxypropyl cellulose (HPC, HPC-L) and saccharin (SAC) were purchased from DFE Pharma (Goch, Germany), Asahi Kasei (Tokyo, Japan), Nippon Soda (Tokyo, Japan) and FUJIFILM Wako Pure Chemical Industries (Osaka, Japan), respectively. Indomethacin (IND) as the API was purchased from Tokyo Chemical Industry (Tokyo, Japan). A small-scale high-shear granulator (55 mL, Fox Sci., Tokyo, Japan) was used to prepare granules. Each powder was mixed in the granulator for 3 min with the formulation shown in Table 1. The granulation was carried out by kneading with adding a binding solution for 10 min and mashing for 47 min at 30 °C. The obtained granules were dried at 60 °C in a vacuum dryer for 2 h. As the binding solution, water or ethanol were used. Ref No. 1-2 and Run No. 1-4 were performed using materials without SAC and all materials, respectively. The demonstrated experimental conditions were shown in Table 1.
Raman spectra were collected using a RamanRxn1 Analyzer with PhAT Probes (Kaiser, MI, USA) during the granulation process. The excitation laser wavelength and the output power were 785 nm and > 150 mW, respectively. The spectra were collected with exposed time of 20 s and cumulated with 1 measurements. The crystal structures of API were analyzed by powder X-ray diffraction (PXRD, RINT-Ultima III, Rigaku, Tokyo, Japan), differential scanning calorimetry (DSC, 8230, Rigaku, Tokyo, Japan) and FT-IR spectroscopy (Jasco, Tokyo, Japan). A flat-faced tablets were compressed with the granules under the conditions of 100 MPa of compression pressure with 200 mg of weight and 8 mm of diameter. The dissolution testing was performed for a tablet by dissolution tester (DT-610, Jasco, Tokyo, Japan) using 900 mL of an acidic aqueous solution (pH 1.2).
Results: Raman spectra of Ref No. 1-2 and Run No 1 were not changed during granulation processes. On the other hand, the peaks due to IND/SAC cocrystal at 1713 cm-1 (carboxylic acid dimer C=O str.) and 1680 cm-1 (benzoyl C=O str.) increased for the sample Run No. 2-4 with the granulation process. Since both IND and SAC have higher solubility in EtOH than H2O, it is can be considered that the surface of the particles dissolves during granulation and forms a cocrystal by interaction at the interface between particles of IND and SAC. In addition, off-line measurements of PXRD, DSC, FT-IR resulted that cocrystal was formed by using EtOH as the binding solution. The solubility of IND was improved by forming cocrystal.
Conclusion: IND/SAC cocrystal was prepared by one-step method of the high shear granulation process using EtOH as the binding solution. The on-line Raman spectra measurements displayed the cocrystal formation process. The built-in quality of cocrystal granules resulted to improve the solubility of IND.