van den Ban Sander, Goodwin Daniel J
GSK Global Manufacturing and Supply, Priory St, Ware, SG12 0DJ, UK.
GSK Research and Development, New Frontiers Science Park, 3rd Avenue, Harlow, CM19 5AW, UK.
Pharm Res. 2017 May;34(5):1002-1011. doi: 10.1007/s11095-017-2115-5. Epub 2017 Feb 10.
The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process.
Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility.
Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability.
The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution.
在制药生产规模下，研究高剪切湿法制粒中颗粒致密化对压片及产品性能的影响。产品性能标准需要与满足可制造性标准的需求相平衡，以确保稳健的工业规模片剂制造工艺。采用质量源于设计的方法来确定压片的过程控制规范，提出崩解和溶出的设计空间，并了解工业压片过程的允许操作限度和所需控制。
通过实验设计（DoE）方法，改变加水量、喷雾速率和湿混时间，制备不同密度（堆积密度）的颗粒。将颗粒压制成不同厚度的片剂，以获得具有不同断裂力的片剂。对所制得的片剂进行崩解和溶出性能评估。通过可压缩性、可压性和成型性来阐释颗粒堆积密度对压片的影响。
压片和产品性能标准对孔隙率提出了相互矛盾的要求。颗粒堆积密度的增加影响了可压性和成型性，并限制了获得具有足够机械强度片剂的能力。片剂固体分数的增加（孔隙率降低）影响了崩解和溶出。规定了基于属性的崩解和溶出设计空间，以实现产品性能和可制造性。
制粒方法及由此产生的颗粒堆积密度是实现现代工业规模药品生产和分销所需的产品性能和可制造性的关键设计考虑因素。
