Preparation of pharmaceutical nanocrystals using wet nanomilling—Hydrotalcite

doi:10.16085/j.issn.1000-6613.2020-2179

Abstract

Abstract:

Low dissolution rate and solubility severely affects their bioavailability and efficacy and is the main factor that led to failure in the development of candidate drug compounds. Recent studies revealed that when the particle size is reduced to around 100—200nm, its dissolution rate and solubility significantly increase. Hydrotalcite is an effective API (active pharmaceutical ingredient) for treating gastric diseases. Its nanoparticle suspension shows a better anti-acid effect and a faster onset of action. In this study, preparation of hydrotalcite nanocrystals using wet nano milling technology was investigated. In the process, sodium hexametaphosphate was selected as a dispersant, and the impacts of dispersant dosage, grinding speed, hydrotalcite content, as well as grinding time on the particle size distribution were examined. An operational envelope was unveiled to obtain a hydrotalcite nano-suspension with D₁₀ (76.4nm), D₅₀(161nm), and D₉₀(352nm) with the grinding speed being 3000r/min, the grinding time 105 minutes, the main drug volume fraction 2%, and the dispersant being 1.5% of the solid content mass fraction. The acid-neutralizing capacity experimental result showed that the dissolution rate of the nano-hydrotalcite suspension in hydrochloric acid was 5 times faster than that of the micron-sized suspension.

Key words: nanomedicine, wet nano milling, hydrotalcite, acid-neutralizing capacity, crystals

摘要：

低溶出速率和溶解度严重影响其生物利用度和药效, 是造成药物研发候选化合物不能成药的首要因素。近年的研究发现，当颗粒粒径减小到100～200nm，其溶出速率和溶解度会出现显著提升。本文研究了利用湿法纳米研磨技术制备铝碳酸镁药物纳米晶体的工艺。铝碳酸镁是治疗胃病的有效药物，其纳米颗粒悬浮液抗酸效果更好，起效速度更快。本文选择了六偏磷酸钠为分散剂，利用湿法研磨机，考察了分散剂用量、研磨转速、铝碳酸镁含量、研磨时间等参数对颗粒粒度分布的影响规律，获得了在最佳的工艺操作条件为研磨转速3000r/min、研磨时间105min、主药体积分数2%、分散剂为固含量质量分数的1.5%时，成功得到粒径D₁₀(76.4nm)、D₅₀(161nm)、D₉₀(352nm)的铝碳酸镁纳米悬浮液。制酸力实验结果证明纳米铝碳酸镁悬浮液比微米级悬浮液在盐酸中的溶出速率快5倍以上。

关键词: 纳米药物, 湿法纳米研磨, 铝碳酸镁, 制酸力, 晶体

CLC Number:

R943

WANG Xiaokang, ZHANG Yang, FALOLA Akinola, HE Yunliang, WANG Xuezhong. Preparation of pharmaceutical nanocrystals using wet nanomilling—Hydrotalcite[J]. Chemical Industry and Engineering Progress, 2021, 40(10): 5699-5707.

王小康, 张扬, FALOLA Akinola, 何运良, 王学重. 湿法纳米研磨制备药物纳米晶体——铝碳酸镁[J]. 化工进展, 2021, 40(10): 5699-5707.

Figures/Tables 13

References 23

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t/min	D₁₀/μm	D₅₀/μm	D₉₀/μm
0	5.32	29.4	114
2	2.04	6.32	72.5
5	1.04	5.43	611
10	0.196	0.552	3.76
15	0.11	0.29	1.06
20	0.104	0.262	0.823
25	0.0981	0.236	0.712
30	0.0897	0.205	0.588
45	0.0832	0.183	0.482
60	0.0798	0.173	0.406
75	0.0772	0.164	0.374
90	0.0763	0.161	0.357
105	0.0764	0.161	0.352

t/min	D₁₀/μm	D₅₀/μm	D₉₀/μm
0	5.32	29.4	114
2	2.04	6.32	72.5
5	1.04	5.43	611
10	0.196	0.552	3.76
15	0.11	0.29	1.06
20	0.104	0.262	0.823
25	0.0981	0.236	0.712
30	0.0897	0.205	0.588
45	0.0832	0.183	0.482
60	0.0798	0.173	0.406
75	0.0772	0.164	0.374
90	0.0763	0.161	0.357
105	0.0764	0.161	0.352

取样时间 /min	铝碳酸镁 /g	水 /mL	盐酸 /mL	氢氧化钠 /mL	制酸力 /mL	制酸时间 /min
0	0.5	87.5	160	28	264	15
2	0.5	87.5	160	26	268	6
5	0.5	87.5	160	28	264	5
10	0.5	87.5	160	22	276	5
20	0.5	87.5	160	10	300	3
30	0.5	87.5	160	12	296	3
60	0.5	87.5	160	16	288	3

取样时间 /min	铝碳酸镁 /g	水 /mL	盐酸 /mL	氢氧化钠 /mL	制酸力 /mL	制酸时间 /min
0	0.5	87.5	160	28	264	15
2	0.5	87.5	160	26	268	6
5	0.5	87.5	160	28	264	5
10	0.5	87.5	160	22	276	5
20	0.5	87.5	160	10	300	3
30	0.5	87.5	160	12	296	3
60	0.5	87.5	160	16	288	3

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