Author links open overlay panel Xi Han, Chinmay Ghoroi, Rajesh Davé
Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t 80 for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings.
Fine particles (<25 μm) have attracted significant interest both from academia and industry. In the pharmaceutical industry fine drug particles have the potential benefit of improved dissolution rate due to their high surface area as indicated by the Noyes-Whitney equation. Micronization often results in high relative cohesion that is largely due to the strong van der Waals force of attraction among dry particles. The highly cohesive nature of the fine powders can lead to downstream processing issues related to their poor flowability and low bulk density.
The importance of flowability of powders for successful manufacture in the food and pharmaceutical industry is well-documented in the literature, especially for fine powders where the flow properties are particularly poor. Traditional methods to improve the powder flow involve aeration, vibration and/or addition of flow agents. However, these approaches typically provide inconsistent or unreliable results and may lead to segregation and non-uniform distribution of the flow additives in the bulk. Over the years, many methods have been developed to improve the flowability of the fine powders. In the pharmaceutical industry, wet and dry granulation are commonly used to increase the granule size and ease the problem of powder handling. This requires additional complex and expensive processing steps and the use of solvents in contrast to a method like direct compaction, which is simple and cost effective. However, when fine, micronized active pharmaceutical ingredients (APIs) are used with an objective of improving dissolution properties, it is likely that other conventional approaches, including granulation may be counter-productive because they may not preserve the increased API surface area.
In order to make direct compaction feasible, APIs and their blends must flow well and have sufficiently high bulk densities. Unfortunately, this cannot be achieved through current approaches for fine API based formulations having greater than 10 or 20% active loadings without employing granulation. Thus it would be desirable to develop approaches that allow for reliable flow improvements and increased bulk densities that can lead to direct compaction formulations at high drug loadings with desirable tablet properties, without requiring dry or wet granulation.
It has been shown by authors’ group that surface modification by dry particle coating is a simple and effective route for improving the flowability of fine powders. In the surface modification by dry coating process, nano-particles are used as guest particles which coat the surface of the host particles and create a nano-scale roughness, hence reducing the cohesive force among dry coated host particles. Previous work also shows that dry coating makes a substantial improvement in the flow properties of the pharmaceutical powders, where the flow function coefficient (a reliable measure of powder flow) and bulk density of these powders fall in the range for direct compaction, based on the previously developed bulk density–FFC phase map. Based on the particle size, there are two different approaches for dry coating. The first approach is usually for particles >25 μm employing a Magnetically Assisted Impaction Coater (MAIC) or a continuously operating cone-mill, or hereafter called comil, where attrition of particle size is kept to a minimum. The second approach, where simultaneous micronization and surface modification is employed using a fluid energy mill (FEM), is suitable for finer particles (<25 μm) including those used in the inhalation application (∼2–5 μm), where materials such as amino acid instead of nano-silica are used for dry coating. Different active pharmaceutical ingredients and excipients have been tested using both approaches with success. In a preliminary investigation using the comil, it was reported that dry coating of API has no negative effect on downstream products and results in improved performance (blend flow property, tablet hardness) when surface modified API is used. In this work, the second approach, which is simultaneous micronization and dry coating in a FEM, is investigated for fine API particles (<25 μm), which is somewhat difficult to achieve in a comil, and the effect on blend properties, direct compaction and tablet dissolution are studied. The FEM is a continuous method that is scalable, and is frequently used in the pharmaceutical industries and has gained significant research interest. Thus it is ideally suitable for the main objective of this work, namely, to investigate the effect of dry coating of fine micronized API powders on dissolution of directly compressed tablets with high drug loading.
Ibuprofen which is a type of Biopharmaceutics Classification System (BCS) class II drug was selected as a model poorly water-soluble drug. In addition, ibuprofen is also known as having poor flow and compaction behavior when it is fine. Although direct compaction is desired, in most cases granulation is performed before tabletting. In order to process ibuprofen via direct compaction, physico-mechanical properties of ibuprofen was changed through simultaneous micronization and surface modification using the nano-silica in the FEM. The dry coated API powders were then formulated into blends with different drug loadings (30%, 60% and 70%). Blends containing fine API particles (∼20 μm) have been studied for their flow properties. Blends containing 50 μm API particles dry coated using the comil are also studied for benchmarking. In addition to the dry coated 20 μm and 50 μm blends, the corresponding uncoated API powder blends are studied for comparison.
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Ibuprofen 50 was purchased from BASF (NY, USA), with volume based d 10, d 50 and d 90 as the following: 16 μm, 58 μm and 148 μm. The excipients included pharmaceutical grade amorphous hydrophilic silica (M5P, Cabot Corporation, MA), microcrystalline cellulose (Avicel PH-102, FMC BioPolymer, Newark, DE), spry dried hydrous lactose (pharmatose DCL-11, DMV, Delhi, NY), magnesium stearate (Mallinckrodt Inc, St Louis, Missouri). Crospovidone (Kollidon-CL) was received as a gift from BASF (Ledgewood, NJ).
In this section, flow characterization results of different blends are first presented for both 20 μm (processed using the FEM) and 50 μm (processed using the comil) blends. The tablet compaction and dissolution results are presented for 20 μm blends with 30% and 60% drug loading.
Representative SEM images of the uncoated and dry coated ibuprofen powders with two different sizes are shown in Fig. 1. The 50 μm ibuprofen has a rod shape and silica coating is observed on the surface of the dry coated
The effect of dry coating of ibuprofen powders on blends as well as tablet properties was investigated. It was shown that blends containing dry coated API powders, particularly micronized (20 μm) have improved flow, packing and compactibility compared to the blends containing uncoated API powders. Both the bulk density and FFC results show clear improvements due to the dry coating for blends made from micronized as well as larger ibuprofen powders with the difference between the dry coated and
The authors gratefully acknowledge the financial support from the National Science Foundation (NSF) through grant #EEC-0540855. The authors would like to thank Dr. David Harris for suggesting blend formulation, Mr. Matthew Mullarney for his input in tablet formation, Dr. Edward Dreyzin for providing access to the Instron, Dr. Daniel To for useful discussions, Freeman Technology for comments regarding the FT4 rheometer results for the blends, and BASF for providing the gift samples of Kollodon-
