Assessment of Resonant Acoustic Mixing for Low-Dose Pharmaceutical Powder Blends.

Obtaining a homogeneous low-dose pharmaceutical powder blend without multi-step processing remains a challenge. One promising technology to address this risk is resonant acoustic mixing (RAM). In this study, the performance of a laboratory resonant acoustic mixer (LabRAM) was studied at low active pharmaceutical ingredient (API) concentrations (0.1-0.5% w/w), using three commercial grades of a model API (Acetaminophen) and diluents with varying physical properties. The performance was assessed by evaluating blend uniformity (BU) and capsule content uniformity (CU) as a function of mixing time. Overall, the LabRAM achieved acceptable BU in a single step even at 0.1% w/w drug loading. A reduction in API primary particle size led to improved mixing efficiency and uniformity. Moreover, the presence of surface cavities in the diluents used appeared to have led to improved uniformity. The results demonstrated that RAM could achieve uniform powder blends without multi-step processing, for low-dose formulations.

On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?

PURPOSE: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. METHOD: Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). RESULTS: This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. CONCLUSIONS: On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.

A compact, portable, re-configurable, and automated system for on-demand pharmaceutical tablet manufacturing.

Due to the complex nature of the pharmaceutical supply chain, the industry faces several major challenges when it comes to ensuring an adequate supply of quality drug products. These challenges are not only the causes of supply chain disruptions and financial loss, but can also prevent underserved and remote areas from receiving life-saving drugs. As a preliminary demonstration to mitigate all these challenges, at MIT we have developed active pharmaceutical ingredients manufacturing in a miniature platform. However, manufacturing of final oral solid dosage as tablets from drug substances had not been demonstrated. In this study, a compact, portable, re-configurable, and automated tablet manufacturing system, roughly the size of a North American household oven, [72.4 cm (length) × 53.3 cm (width) × 134.6 cm (height)] was designed, built and demonstrated. This miniature system is able to manufacture on-demand tablets from drug crystals on a scale of hundreds to thousands per day. Ibuprofen and Diazepam, each having different drug loading, were manufactured using this miniature system and meet U.S. Pharmacopeia standards. We foresee this flexible, miniature, plug-and-play pharmaceutical solids dosage manufacturing system advancing on-demand ready-to-use pharmaceuticals enabling future treatment of human diseases at the point-of-care.

Investigation of an 11mm diameter twin screw granulator: Screw element performance and in-line monitoring via image analysis.

As twin screw granulation (TSG) provides one with many screw element options, characterization of each screw element is crucial in optimizing the screw configuration in order to obtain desired granule attributes. In this study, the performance of two different screw elements - distributive feed screws and kneading elements - was studied in an 11 mm TSG at different liquid-to-solid (L/S) ratios. The kneading element configuration was found to break large granules more efficiently, leading to narrower granule size distributions. While pharmaceutical industry shifts toward continuous manufacturing, inline monitoring and process control are gaining importance. Granules from an 11 mm TSG were analysed using the Eyecon™, a real-time high speed direct imaging system, which has been used to capture accurate particle size distribution and particle count. The size parameters and particle count were then assessed in terms of their ability to be a suitable control measure using the Shewhart control charts. d10 and particle count were found to be good indicators of the change in L/S ratio. However, d50 and d90 did not reflect the change, due to their inherent variability even when the process is at steady state.

Effects of powder flow properties on capsule filling weight uniformity.

Filling capsules with the right amount of powder ingredients is an important quality parameter. The purpose of this study was to develop effective laboratory methods for characterizing flow properties of pharmaceutical powder blends and correlating such properties to weight variability in filled capsules. The methods used for powder flow characterization were bulk and tapped density, gravitational displacement rheometer (GDR) flow index, Freeman Technology V.4 (FT4) powder rheometer compressibility, FT4 basic flow energy (BFE), and cohesion parameters [cohesion, (C) and flow factor (ffc)] measured in a shear cell also using the FT4. Capsules were filled using an MG2-G140 continuous nozzle dosator capsule-filling machine. Powder flow properties were the most predominant factors affecting the weight and weight variability in the filled capsules. Results showed that the weight variability decreased with increasing bulk and tapped density, ffc and BFE, while the weight variability increased with increasing compressibility, cohesion and GDR flow index. Powder flow properties of the final blends were significantly correlated to the final capsule weight and weight variability of the filled capsules.