Sample Size Requirements of a Pharmaceutical Material Library: A Case in Predicting Direct Compression Tablet Tensile Strength by Latent Variable Modeling

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this work, the direct compression process was taken as the research object, and the effects of different sample sizes of material libraries on partial least squares (PLS) modeling in the prediction of tablet tensile strength were investigated. A primary material library comprising 45 materials was built. Then, material subsets containing 5 × i (i = 1, 2, 3, …, 8) materials were sampled from the primary material library.

Each subset underwent sampling 1000 times to analyze variations in model fitting performance. Both hierarchical sampling and random sampling were employed and compared, with hierarchical sampling implemented with the help of the tabletability classification index d. For each subset, modeling data were organized, incorporating 18 physical properties and tableting pressure as the independent variables and tablet tensile strength as the dependent variable. A series of chemometric indicators was used to assess model performance and find important materials for model training. It was found that the minimum R² and RMSE values reached their maximum, and the corresponding values were kept almost unchanged when the sample sizes varied from 20 to 45.

When the sample size was smaller than 15, the hierarchical sampling method was more reliable in avoiding low-quality few-shot PLS models than the random sampling method. Two important materials were identified as useful for building an initial material library. Overall, this work demonstrated that as the number of materials increased, the model’s reliability improved. It also highlighted the potential for effective few-shot modeling on a small material library by controlling its information richness.

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Materials

A total of 45 powdered materials, including 32 pharmaceutical excipients and 13 natural production powders (NPPs), were carefully selected from a homemade database named intelligent TCM (iTCM) [4,37]. Different batches or types of the same material, exhibiting different capacities, were considered in the material library. For instance, seven types of MCC powders, including PH102, PH200NF, Oricel™PH-102 SCG, Oricel™PH302NF, Oricel™PH-112, Oricel™PH302NF, and vivapur® type200, were included. These 45 samples were used as the primary material library and were divided into 5 categories (Cat.1, 2A, 2B, 2C, 3; Cat.1 denotes Category 1, and the same nomenclature applies to the others) by the tabletability index d. Each category included 9 samples. The names, lot numbers, and suppliers for all materials are described in Table S2 in the Supplementary Materials.

Table S2. The information for 45 materials including names, abbreviations, batch numbers suppliers and physical attributes.

Name	Abbreviation	Batch number	Supplier
Microcrystalline Cellulose vivapur® type200	MCC	5620030813	JRS Pharma GmbH&Co. KG
Microcrystalline Cellulose PH200NF	MCC	P0200J1511	SSP, China-Germany joint venture
Microcrystalline Cellulose OricelTM PH-102 SCG	MCC	P0102F1506	SSP, China-Germany joint venture
Microcrystalline Cellulose OricelTM PH302NF	MCC	P0102D1509	SSP, China-Germany joint venture
Microcrystalline Cellulose OricelTM PH-112	MCC	5610237731	SSP, China-Germany joint venture
MCC PH102	MCC	NO.2565	Asahi Kasei Chemicals Corporation
Microcrystalline Cellulose OricelTM PH302NF	MCC	P0302F1509	SSP, China-Germany joint venture
Ethylcellulose N-7 Pharm	EC	44156	Ashland_Aqualon, Kentucky
Hydroxypropyl methylcellulose E5LV	HPMC	3G190124L1	The Dow Chemical Company
lactose Cellactose® 80	Lac	L1533	Molkerei Meggle Wasserburg GmBH & Co. KG
Croscarmellose sodium	CMC-Na	X5G248	Nichirin chemical industries LTD
Hydroxy propyl methyl cellulose E3LV	HPMC	2E150124L2	The Dow Chemical Company
Calcium carboxymethylcellulose ECG505	CMC-Ca	E4I086	Nichirin chemical industries Ltd.
Radix Rehmanniae Recens extract	Sheng dihuang	SDH201609	Beijing Tcmages Pharmaceutical Co., Ltd.
Herba Ecliptae extract	Mo Hanlian	MHL201609	Beijing Tcmages Pharmaceutical Co., Ltd.
processed Radix Glycyrrhizae extract	Zhi gancao	ZGC201609	Beijing Tcmages Pharmaceutical Co., Ltd.
Rhizoma Belamcandae extract	She gan	SG201609	Beijing Tcmages Pharmaceutical Co., Ltd.
Radix Angelicae Sinensis extract	Dang gui	DG21609	Beijing Tcmages Pharmaceutical Co., Ltd.
lactose Tablettose® 80	Lac	L1543	Molkerei Meggle Wasserburg GmBH & Co. KG
lactose Flowlac® 100	Lac	L1517	Molkerei Meggle Wasserburg GmBH & Co. KG
lactose Pharmatose® 110M	Lac	1009CON	DFE Pharma
lactose anhydrous 21 AN	Lac	1007NX8	DFE Pharma
lactose Granulac® 200	Lac	L1535	Molkerei Meggle Wasserburg GmBH & Co. KG
lactose Spherolac® 100	Lac	L1413	Molkerei Meggle Wasserburg GmBH & Co. KG
lactose Granulac® 70	Lac	L1533	Molkerei Meggle Wasserburg GmBH & Co. KG
Croscarmellose sodium	CMC-Na	10082Fo	DFE Pharma
Calcium phosphate dehydrate	/	1286C350	Avantor Performance Material Strading (Shanghai) Co.Ltd.
lactose anhydrous Duralac® H	Lac	LC042-5-805	Molkerei Meggle Wasserburg GmBH & Co. KG
lactose Pharmatose® 200M	Lac	10095MW	DFE Pharma
Pregelatinized starch	/	NO60820327	Asahi Kasei Chemicals Corporation
Dextrin	/	170307	Beijing Biotopped Technology Co., Ltd.
Sodium bicarbonate	NaHCO3	A038821	Acros Organics Co., Ltd.
Calcium phosphate dibasic	CaHPO₄	A0345625	Acros Organics Co., Ltd.
Radix Scutellariae extract	Huang qin	HQ201609	Beijing Tcmages Pharmaceutical Co., Ltd.
Radix Glycyrrhizae extract	Sheng gancao	SGC201609	Beijing Tcmages Pharmaceutical Co., Ltd.
Rhizoma Ligustici extract	Chuan xiong	CX201609	Beijing Tcmages Pharmaceutical Co., Ltd.
Carboxy methyl starch sodium	CMS-Na	C10072096	Shanghai Macklin Biochemical Co.,Ltd.
Carboxy methyl starch sodium	CMS-Na	C10051641	Shanghai Macklin Biochemical Co.,Ltd.
Croscarmellose sodium Vivasol®	CMC-Na	3201061016	JRS Pharma GmbH&Co. KG
Corn starch	/	MKBW7231V	Merck KGaA, Darmstadt
Radix Paeoniae Rubra extract	Chi shao	CS20180704	Beijing Tcmages Pharmaceutical Co., Ltd.
Moutan Cortex extract	Mu danpi	MDP20180704	Beijing Tcmages Pharmaceutical Co., Ltd.
Coptidis Rhizoma extract	Huang lian	HL20180704	Beijing Tcmages Pharmaceutical Co., Ltd.
Radix Ploygoni Multiflori semi-extract	He shouwu	ZHSWB20190124	Beijing Tcmages Pharmaceutical Co., Ltd.
Radix Ploygoni Multiflori blend	He shouwu	ZHSWH20190124	Beijing Tcmages Pharmaceutical Co., Ltd.

 

Cao, J.; Shen, H.; Zhao, S.; Ma, X.; Chen, L.; Dai, S.; Xu, B.; Qiao, Y. Sample Size Requirements of a Pharmaceutical Material Library: A Case in Predicting Direct Compression Tablet Tensile Strength by Latent Variable Modeling. Pharmaceutics 2024, 16, 242. https://doi.org/10.3390/pharmaceutics16020242

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