Darweish Eman, Marzouk Hoda M, Fayez Yasmin M, Eissa Maya S
Egyptian Russian University, Faculty of Pharmacy, Pharmaceutical Chemistry Department, Badr City, Cairo 11829, Egypt.
Cairo University, Faculty of Pharmacy, Analytical Chemistry Department, Kasr Al-Aini St, Cairo 11562, Egypt.
J AOAC Int. 2022 Dec 22;106(1):14-25. doi: 10.1093/jaoacint/qsac092.
Irritable bowel syndrome (IBS) is a common disorder leading to undesirable pain. Phloroglucinol (PHG) and trimethylphloroglucinol (TMG) are co-formulated as spasmolytic medication that is considered to be effective in reducing smooth muscle spasm. 3,5-Dichloroaniline (DCL) is a specified PHG pharmacopoeial impurity which needs to be monitored to avoid its toxic effects.
Different smart approaches are presented to provide simple, reliable, and economic spectrophotometric methods able to resolve the severe overlap in the spectra of PHG and TMG in their pure and pharmaceutical forms, in addition to their estimation in the presence of DCL as a toxic impurity of PHG without any need for initial separation.
The presented work includes univariate methods, derivative ratio (DR), ratio difference (RD), mean centering (MCR) and deconvulated Fourier method (DF), which were able to determine PHG and TMG simultaneously in their binary mixture. Firstly, DCL was estimated in the zero order, where the two drugs have zero absorption at 247.0 nm, and then its contribution was eliminated by applying ratio subtraction method. Multivariate chemometric partial least squares (PLS) and principal component regression (PCR) models were also applied to determine PHG and TMG simultaneously in the presence of the impurity, DCL.
Univariate methods were applied in the range 5.0-30.0, 2.5-25.0, and 1.0-12.0 µg/mL for PHG, TMG, and DCL, respectively. The proposed chemometric models were used in the range 6.0-14.0, 5.0-25.0 and 2.0-10.0 µg/mL for PHG, TMG, and DCL, respectively. These analytical approaches succeeded in estimating the cited drugs in their pharmaceutical formulation and assessing content uniformity of dosage units. The methods were statistically compared with a reported HPLC method, and the results revealed no significance statistical difference.
This work provides for the first time successful univariate and multivariate PLS and PCR methods to assess PHG and TMG in the presence of DCL as a toxic impurity along with content uniformity testing of dosage units.
Comparative univariate and multivariate spectrophotometric analytical approaches are presented, for the first time, for estimation of spasmolytic formulation of PHG and TMG in the presence of DCL as a PHG toxic impurity. Successful application to content uniformity testing of Stopspasm® dosage form is demonstrated. A statistical study, including t-tests and one-way analysis of variance (ANOVA), was conducted.
肠易激综合征（IBS）是一种导致不良疼痛的常见病症。间苯三酚（PHG）和三甲基间苯三酚（TMG）联合制成解痉药物，被认为可有效减轻平滑肌痉挛。3,5 - 二氯苯胺（DCL）是PHG的一种特定药典杂质，需要进行监测以避免其毒性作用。
提出了不同的智能方法，以提供简单、可靠且经济的分光光度法，能够解决PHG和TMG纯品及药物制剂形式光谱的严重重叠问题，此外还能在存在作为PHG有毒杂质的DCL的情况下对其进行测定，而无需进行初始分离。
所开展的工作包括单变量方法、导数比（DR）、比差（RD）、均值中心化（MCR）和去卷积傅里叶方法（DF），这些方法能够同时测定二元混合物中的PHG和TMG。首先，在零阶光谱中测定DCL，此时两种药物在247.0 nm处无吸收，然后通过应用比值减法消除其影响。还应用了多变量化学计量学偏最小二乘法（PLS）和主成分回归（PCR）模型，以在存在杂质DCL的情况下同时测定PHG和TMG。
单变量方法分别在5.0 - 30.0、2.5 - 25.0和1.0 - 12.0 μg/mL范围内用于测定PHG、TMG和DCL。所提出的化学计量学模型分别在6.0 - 14.0、5.0 - 25.0和2.0 - 10.0 μg/mL范围内用于测定PHG、TMG和DCL。这些分析方法成功地测定了药物制剂中所述药物，并评估了剂量单位的含量均匀度。将这些方法与报道的高效液相色谱法进行了统计学比较，结果显示无显著统计学差异。
本研究首次成功提供了单变量以及多变量PLS和PCR方法，用于在存在作为有毒杂质的DCL的情况下评估PHG和TMG，并对剂量单位进行含量均匀度测试。
首次提出了比较单变量和多变量分光光度分析方法，用于在存在作为PHG有毒杂质的DCL的情况下测定PHG和TMG的解痉制剂。证明了该方法在Stopspasm®剂型含量均匀度测试中的成功应用。进行了包括t检验和单因素方差分析（ANOVA）在内的统计研究。
