In situ monitoring of the crystalline state of active pharmaceutical ingredients during high-shear wet granulation using a low-frequency Raman probe

Abstract

Optimization of manufacturing processes based on scientific evidence is important in the quality control of active pharmaceutical ingredients (APIs) and drug products, particularly when crystal forms change during production, which could affect subsequent drug performance. In this study, we verified crystalline states using various crystal faces and excipients during high-shear wet granulation based on non-contact low-frequency (LF) Raman probe monitoring. Four model drugs [indomethacin (IND), acetaminophen (APAP), theophylline (TP), and caffeine (CAF) polymorphs and cocrystals] were mixed with microcrystalline cellulose and hydroxypropyl cellulose with the addition of water over time. The LF Raman probe showed comparatively high sensitivity in monitoring 5–20% APAP and IND in a wet mass. Notably, as observed from the characteristic LF Raman peak shifts, form I TP and CAF and their cocrystals were more susceptible to transformation to the monohydrate form than form II. This method was also shown to be applicable in monitoring a commercial formulation of eight excipients and revealed crystalline transformations after 15 min of mixing. Therefore, probe-type LF Raman spectroscopy can be successfully employed to distinguish and monitor the crystalline state of APIs in real time during high-shear wet granulation, in which there is a risk of crystal transformation.

Introduction

In recent years, the optimization of manufacturing processes based on scientific evidence has become acknowledged as an important pre-requisite for the quality control of active pharmaceutical ingredients (APIs) [1], [2], [3]. It is necessary to strengthen quality assurance by focusing on the control of process parameters and critical quality attributes (CQAs), which can improve efficiency and reduce the risks associated drug development and manufacturing processes. In order to accurately identify process parameters and CQAs, real-time analysis using various process analytical technology (PAT) tools has been widely studied and applied [4], [5], [6]. Examples of PAT tools used in conjunction with the wet granulation process include near-infrared spectroscopy (NIR), Raman spectroscopy, and focused beam reflectance methods [7], [8], [9], among which, NIR can extract information linked to CQAs from the obtained spectra by using processing software coupled with data analysis methods, such as multivariate analysis. Additionally, NIR has been applied to evaluate the mixing homogeneity of drugs and excipients, and to measure moisture and drug contents during the manufacturing process [10], [11], [12]. However, the high sensitivity of NIR to water absorbance can be a distinct disadvantage, as the O-H band interferes with other obtained bands [13]. Accordingly, it would be highly desirable to develop PAT tools that are insensitive to moisture and specialized for discriminating crystal form. In general, NIR and Raman spectroscopy can both be used as PAT tools for identifying crystal polymorphisms. Raman spectroscopy, which includes conventional and low-frequency (LF) types, is a commonly used technique for polymorph characterization and formulation analysis due to its advantages in terms of minimal interference from water and larger signal strength from most aromatic APIs than from aliphatic excipients [14].

Whereas conventional Raman spectroscopy can be used to obtain information on the chemical structure of a compound based on spectra derived from the bond vibration between atoms, the LF type can be specifically employed to obtain information on crystal form, packing arrangement, and intermolecular forces based on spectra derived from the lattice vibration of crystals [15], [16], [17]. We have previously reported the utility of LF Raman spectroscopy with respect to the identification of crystalline drugs alone and in tablet form, the identification of pharmaceutical excipient polymorphism, and the monitoring of crystal form transition of drugs and cocrystals under various conditions of temperature, solvent used, and drug ratio, as well as its practical use as a PAT tool for in situ monitoring of the crystal state in suspension and fluidized bed granulators [18], [19], [20], [21].

Granulation, which can be achieved by either wet or dry methods, is an important process in the manufacture solid dosage form drugs. Wet granulation is used to improve powder properties and generally entails the addition of a liquid binder or water, and is thus characterized by high humidity conditions during agitation in different machines, such as tumbling mixers, and fluidized bed or high-shear mixer granulators. Compared with other mixer types, high-shear mixer granulators, which comprise an impeller and chopper and generate high shearing forces, have the advantages of a shorter processing time, more effective liquid binder addition, and the production of particles that are characteristically small, dense, and spherical. The process is subject to formulation and process design (e.g., binder properties and operating parameters) [22], [23], [24], [25], given that under extreme moisture conditions (up to 50% w/w of the dry powders [26]), such processes could lead to changes in particle size and, potentially, a transition of crystalline form. Crystal polymorphism affects the physical properties of APIs, including their solubility [27], thereby substantially affecting production processes, and the stability, quality, efficacy, and safety of the drug products. It is thus necessary to select the appropriate crystal form and strictly control its consistency. Furthermore, real-time detection and monitoring are important at every step in modern pharmaceutical development [25]. Moreover, from the perspective of patent litigation relating to the crystal polymorphism of marketed products, product development without infringing patents will be a requirement additional to quality assurance.

In the present study, we were interested in investigating the in situ monitoring of API transformation during high-shear wet granulation in the presence of excipients using a non-contact LF Raman probe under different circumstances. Initially, we examined the practical sensitivity of the probe using two APIs with no crystal form transition during wet granulation, followed by hydrate transition of the reported API (theophylline form II [24]). The next scenario we examined was cocrystal dissociation under conditions of extreme humidity, as the poor water solubility of compounds is invariably a concern in the pharmaceutical industry [28], and can be improved by the appropriate design of cocrystals [29], [30], [31]. However, temperature and humidity have been reported to have an influence on cocrystal dissociation during storage (theophylline and glutaric acid at 40 °C/75% RH mixed with microcrystalline cellulose) [32], [33]. Moreover, wet granulation, which temporarily entails high humidity conditions due to the addition of a solute, could possibly result in a change in cocrystal form [34].

Finally, drug products contain not only APIs and binders, but also various excipients such as disintegrants, lubricants, and glidants. Currently, generic products are being developed by many pharmaceutical companies with the aim of reducing costs, which will lead to the rational selection of generic additives that differ from those in the original products. For this reason, monitoring via LF Raman spectroscopy during wet granulation has been used to examine numerous different excipient compositions for comparison with the original drug. In this study, using the estimated generic formulation of “Theolong tablet 50 mg” (Eisai Co., Ltd. Tokyo, Japan) as a model, we investigated whether crystal form and its transformation can be monitored in a marketed product that contains eight excipients.