All4Nutra
Abstract
Lactose is an excipient used extensively for bulking, diluting, and molding active pharmaceutical ingredients in tablet manufacturing. Particularly, granulated lactose (GL) intended for direct powder compression has distinct properties due to differences in manufacturing methods. It contributes to handling blended powders for tableting and tablet quality. In this study, we aimed to compare the functions of different forms of GL added as excipients during direct powder compression on the tablet properties and the effect of magnesium stearate (Mg-S) used as a lubricant on each type of GL. Different GL types obtained using different manufacturing methods (agitated granulation, GL-AG; spray-dried granulation, GL-SD; fluidized bed granulation, GL-FB) were blended with maize starch, low-substituted hydroxypropyl cellulose, and paracetamol in a V-type blender for 10 min. Mg-S was added at varying amounts (0.1, 1.0, and 2.0%) and blending times (5, 10, and 30 min) for the nine types of blended powders for tableting formulation. The powders were tableted, and the tablets were evaluated for weight and drug loading variations, tensile strength, friability, and disintegration time. When tablets with the same blending conditions were compared, the tensile strength and disintegration time were in the order of GL-FB > GL-SD > GL-AG. For each GL, we analyzed the effects of changes in the added amount of Mg-S and blending time using contour plots, evaluated the effects of blending conditions on tablet properties, and determined the target tablet properties. We investigated the optimization of the lubricant blending conditions to obtain suitable tablets.
Introduction
Tablets are the most frequently used dosage forms because they are advantageous for packaging, transportation, and storage, can be prescribed in counting units when dispensing, and are easy for patients to use. Wet granule compression is a commonly used method in tablet manufacturing.1–3) This method comprises many steps from the raw material to the final product and is labor and time-intensive.4)
There is a global commitment to carbon neutrality by 2050 following the United Nations Framework Convention on Climate Change. The first goal is to reduce greenhouse gas emissions by 46% from the levels in 2013 by 2030. This carbon-neutral challenge is being promoted globally as it will lead to changes in industrial structure.5) In tablet manufacturing using the granule compression method, various trial granulations are conducted to establish the granulation conditions in the early stage of development. In addition, in commercial production, it is necessary to uniformly mix the active ingredient and multiple additives immediately before granulation on a production line. However, these requirements can be avoided by using granules consisting only of pure lactose, which likely reduces the considerable time and energy typically required for these processes. Under these circumstances, direct powder compression is more advantageous than wet granule compression in terms of the required work steps, time, and energy consumption. In the future, this tableting method will attract increasing attention from global companies that require decarbonized management.6,7) Consequently, the development of additives used in direct powder compression and investigation of tableting conditions have increased.8–14)
Granulated lactose (GL), intended for use in direct powder compression, has significantly different properties depending on the granulation method and is thought to contribute to handling powder formulations and tablet quality. The correct selection of GL is important to satisfy robustness at a high level when manufacturing solid formulations using a high-speed tableting machine.15–17)
Lubricants are indispensable additives for improving tablet quality and manufacturing productivity.18) Magnesium stearate (Mg-S) is a commonly used lubricant. However, because it is a highly spreadable hydrophobic compound,19) it may decrease tablet tensile strength,20,21) extend the disintegration time,22) and slow the dissolution rate.23,24) These factors, in turn, affect the in vivo pharmacokinetics of the drug formulation. The quantity of Mg-S added and blending time is important considerations during tablet formulation. However, to date, most Mg-S addition conditions have been based on empirical judgments, and clear indicators regarding the form of excipients and the effects of Mg-S on tablet properties have yet to be determined.
In this study, we compared the functions of different forms of GL added as excipients during direct powder compression on the tablet properties and the effect of Mg-S on each type of GL. Then, the GL species selection and lubricant blending conditions were examined to obtain the tablet properties required as an actual product.
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Materials
Three types of GL, agitated granulation lactose (GL-AG, Tablettose® 80, Meggle, Wasserburg, Germany), spray-dried granulation lactose (GL-SD, FlowLac® 100, Meggle), and fluidized bed granulation lactose (GL-FB, Dilactose® S, Freund Corp., Tokyo, Japan), were used as fillers. The model drug was Paracetamol (AP, Maruishi Pharmaceutical Co., Ltd., Osaka, Japan). AP was obtained by classifying No. 42 (355-µm mesh) and No. 100 (150-µm mesh) sieves using a vibratory sieve shaker (Analysette, Fritsch, Idar-Oberstein, Germany) for 30 min. AP with a particle size of 150 − 355 µm was used in the experiments. Low-substituted hydroxypropyl cellulose (L-HPC, LH-21, Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) and maize starch (MS, Nihon Shokuhin Kako Corp., Tokyo, Japan) were used as disintegrants. The lubricant was magnesium stearate (Mg-S, vegetable, FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan).
Shohei Nakamura, Nanami Ito, Ayumi Sakurada, Takatoshi Sakamoto, Effects of Granulated Lactose Characteristics and Lubricant Blending Conditions on Tablet Physical Properties in Direct Powder Compression, J-Stage, Chemical and Pharmaceutical Bulletin, https://doi.org/10.1248/cpb.c23-00262
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