(2lr) Exploring API Impregnation Technology with a Case Study on Carbamazepine

Introduction and background: Impregnation is a widely employed technique for incorporating chemicals, including drugs, into the pores of a host particle. This process involves using a drug solution or dispersion to effectively deposit the desired substances within the particle structure. The technology primarily entails dissolving the pharmaceutical substance in a suitable volatile organic solvent. The resulting solution is then applied to a permeable substrate, which facilitates its transportation into the pores through capillary action, effectively displacing any gas that might be present. Subsequently, the particles undergo a drying process to promote solvent evaporation, resulting in the formation of a dry porous carrier impregnated with the drug. Impregnation in the context of pharmaceutical manufacturing offers several notable advantages, as follows: Firstly, the impregnation process enables the dissolution of the active pharmaceutical ingredient (API) regardless of its particle size. This attribute is particularly significant as it eliminates the need to consider API particle size as a contributing factor. Secondly, the impregnation and drying processes can be efficiently performed simultaneously in a single step, thereby streamlining the manufacturing process and enhancing overall productivity. Thirdly, standard fluid bed equipment is adept at accommodating high-capacity systems exceeding 100 Kg/h, thereby facilitating large-scale production capabilities and meeting the demands of the pharmaceutical industry. Furthermore, the carrier material, once impregnated, exhibits an elevated degree of flowability and compactibility, which in turn contributes to the ease and efficacy of subsequent processing steps. The subsequent post-processing phase is characterized by its simplicity, involving solely capsule filling or compression. Moreover, it is worth noting that the impregnation process preserves the surface properties of the carrier material, effectively eliminating the segregation of API and excipient. This characteristic ensures the integrity and uniformity of the final product. One notable consequence of the impregnation process is the consequential increase in the specific surface area (SSA) of the impregnated API, thereby leading to enhanced dissolution characteristics. This improvement in dissolution rates is particularly beneficial for pharmaceutical formulations. Additionally, the API solution exhibits a uniform distribution across solid particles, thereby contributing to high content uniformity, regardless of the drug loading percentage, which can range from 0.1% to 30%. This uniformity is a crucial aspect in ensuring the consistency and effectiveness of pharmaceutical preparations. This study employed fundamental methodologies to facilitate the successful impregnation of carbamazepine into porous carriers. Additionally, it elucidated the specific criteria pertaining to the essential equipment and materials needed to accomplish this objective. A comprehensive suite of analytical methodologies was investigated to achieve a thorough characterization of the impregnated products.

Materials and methods: In this study, carbamazepine was selected as the active pharmaceutical ingredient (API), and Neuslin (NEU) was chosen as the porous carrier. The initial step involves dissolving carbamazepine in acetone at different concentrations (1%, 7%, and 12%). The mixing process was performed at various temperatures to attain the maximum drug concentration within the solution. The resulting solvent was subsequently sprayed into the Glatt FB (Fluid Bed) dryer. Following this, the fluidized bed process parameters, including spray rate, temperature, and fluidizing time, were optimized to achieve the maximum loading. The particle size distribution (PSD) was analyzed to determine if any changes were caused by particle fragmentation, particle agglomeration, particle coating, or spray drying. Scanning electron microscopy was applied for investigation of morphology analysis before and after impregnation. X-ray diffraction analysis was conducted to determine the crystallinity of API during impregnation. In addition, capsule and tabled were made by impregnated carriers and some of physical and mechanical properties was measured. The dissolution experiment was conducted using a dissolution apparatus, with the drug substance dissolved in 1000 ml of deionized water mixed with 1% SLS, maintained at a temperature of 37°C and stirred at 50 rpm. To collect samples for analysis, a peristaltic pump was connected to the dissolution apparatus, allowing withdrawal of samples at specified time intervals of 3 minutes over a duration of 120 minutes.

Results: The successful loading of API (Active Pharmaceutical Ingredient) with maximum 30% into in Neusilin porous carrier was achieved. The findings of this study demonstrated that the impregnated products maintained an identical particle size distribution (PSD) to that of pure Neusilin, thereby implying the effective encapsulation of the drug within the Neusilin pores. Moreover, the results provided conclusive evidence ruling out the occurrence of spray coating, agglomeration, or fines resulting from particle attrition. The release profile of the carbamazepine in its pure crystal powder form demonstrated a minimal release of less than 1% within the initial 3minute interval. In contrast, the impregnated product exhibited a significantly higher release of approximately 40% of carbamazepine during the same 3minute period. Results shows that capsules filled with impregnated Neusilin (60mg) released 80% drug in 17minutes and tablets made with impregnated Neusilin (60mg) released 80% in 27mins. whereas only 28% of the pure carbamazepine was dissolved within the same time frame. In addition, capsules of 240mg of impregnated carbamazepine released 75% within 17 minutes in 4.5 pH phosphate buffer. These findings highlight the potential effectiveness of impregnation as a valuable approach for enhancing the solubility of drugs with limited solubility, exemplified by carbamazepine in this study. XRD results showed that API is amorphous which promote the dissolution rate. A detailed analysis of the SEM images reveals that the impregnated products exhibit a well-defined spherical morphology, which is crucial for ensuring optimal flow properties. The SEM images of the impregnated product closely resemble those of pure NEU, indicating that the process of loading and drying the drug particles within the carrier does not lead to any observable changes in the external morphology of the carrier particles. Importantly, there is no apparent evidence of granulation, agglomeration, or coating of the carrier particles during the impregnation process, suggesting the preservation of the carrier's original physical characteristics.

Conclusion and future directions: The results of impregnation of carbamazepine showed several advantages. Firstly, it is simple to run, indicating that it is user-friendly and can be easily operated. Additionally, the parameters of the FB dryer can be manipulated to achieve different results, providing flexibility in API loading. By adjusting the spray time, a wide range of API loading levels can be achieved. Preliminary results indicate that the process runs smoothly, with no fines generated by attrition, spray coating, or agglomeration. This is a positive outcome as it ensures that the product remains intact without any unwanted particles or aggregates. Despite the fact that the production of all types of drugs with an amorphous structure requires special methods, this is notwithstanding that this simple process has successfully changed the structure of the drug from crystalline to amorphous without resulting in any significant modifications in its chemical composition. This amorphization of the impregnated API significantly shortened its release time and made it possible to manufacture a capsule formulation of the drug. In addition, the ability of impregnation process to achieve very high blend uniformity regardless of the amount of API loading, was confirmed in this study.