Original Article APPLICATION OF NEAR INFRARED SPECTROSCOPY FOR ENDPOINT DETERMINATION OF BLENDING AND INFLUENCE OF LOADING ORDER PATTEERA SODATA 1 , JOMJAI PEERAPATTANA 2 * 1 Novel Drug Delivery Systems Development Center, Faculty of Pharmacy, Thammasat University, Pathumthani 12120, Thailand, 2 Center for Research and Development of Herbal Health Products, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand Email: jomsuj@kku.ac.th Received: 02 Jul 2020, Revised and Accepted: 24 Aug 2020 ABSTRACT Objective: This study aimed to apply near-infrared spectroscopy along with a thief as a tool to determine the endpoint of the blending process. Methods: The calibration model was constructed by partial least square regression. The best model was applied to determine the endpoint of the blending process, also the effect of loading order on the endpoint for the blending of the formulation containing a low concentration of the active pharmaceutical ingredient. Results: The best partial least square regression model yielded the lowest root mean square error of calibration of 1.4004, the lowest root mean square error of prediction of 1.4108 and the highest correlation coefficient of 0.9921. Validation study revealed the reference values were not statistically different from those of the predicted values. The model could predict the endpoint of the blending process with acceptable precision and accuracy. Standard deviation of the content of active pharmaceutical ingredients was ≤ 3% of the target after eighteen minutes of the blending process, which indicated the uniformity of powder blends. Additionally, the model revealed the order of powder loading slightly affected the blending time. The protocol that loaded the active pharmaceutical ingredient first or last needed a longer time to achieve the uniformity of blend. Conclusion: NIR spectroscopy is the rapid and effective tools that could be applied to study the blending process in the pharmaceutical manufacturing. Keywords: Near-infrared spectroscopy, Partial least square regression, Blend uniformity, Order of powder loading © 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijap.2020v12i6.38916. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Uniformity of blend is part of the critical steps in the production of solid dosage forms to ensure the content uniformity of the finished product [1, 2]. It is particularly important for a dosage form containing a low concentration of active pharmaceutical ingredient (API) or highly potent drugs. Non-uniformity of powder blends can cause excess or non-adequate API content, which affects the quality, safety and efficacy of pharmaceutical products. In-process control of blending is an important process needed to ensure uniformity and quality of bulk product during a manufacturing step, before transfer to succeeding unit operation processes. To test the uniformity of powder blends, the sample was taken by a thief and then tested by analytical methods such as UV-visible spectrophotometry or high-performance liquid chromatography. A thief sampling method has been widely used in the pharmaceutical industry. Although it has limitations such as it can induce a bias in the results, but this method is easy, convenient and still generally accepted in a study for determination of blend uniformity in most pharmaceutical manufactures. With respect to sample analysis, the conventional methods have been utilized for a long time, but they have limitations, i.e. it needs sample preparation, which is time-consuming, require expensive laboratory analyses, increases chemical exposure of the operators and non-environmentally friendly. Therefore, the method which has sufficient accuracy, reliability, speed and convenience might be applied to determine the uniformity of blend. There are studies applied near-infrared (NIR) spectroscopy as a tool for monitoring the uniformity of powder blends [1, 3, 4]. NIR spectroscopy is a non-destructive and non-invasive analytical technique being a more robust, consistent and rapid tool [5]. Samples can be analyzed without any preparations. Precise data can be obtained by correlating spectral data to identify or quantify a component by chemometric methods. The most widely used chemometric methods were partial least square (PLS) regression and principal component analysis [6]. NIR spectroscopy has been widely applied in the agricultural, food and beverage industries [7, 8]. For pharmaceutical industry field, NIR spectroscopy along with chemometric methods can be applied for both qualitative and quantitative analysis such as API content, excipient content [9, 10], drug stability [11] state of solid material [12] and identification of herbal extract [13, 14]. Furthermore, NIR spectroscopy is an effective tool for enabling the real-time release of pharmaceutical products. It has found increasing use in the monitoring of blend, granulation, moisture content, drying operations, tableting and other unit operations [15-19]. Many studies developed innovation blend monitoring by using a fiber optic NIR-probe mounted on the blender [20-23]. But the question was the number of probes they used is sufficient to predict the blending accurately. Moreover, the location of probes is important. The probe should be mounted onto various areas of the blender, i.e. top, bottom, each side, including the critical locations such as the edge of the chamber. Different types of blender need different points to set a NIR-probe. This results in an expensive investment. NIR spectroscopy is limited by the sampling position and only provides information regarding the surface region of the powder blends [1]. Therefore, the application of a thief sampling along with NIR spectroscopy might provide a convenient and inexpensive tool to create a robust model for quality assurance. This method provides a more rapid batch release. The manufacturer could apply the NIR spectroscopy with a thief for in-process control, process validation, process re-validation, including other quality assurance issues. This study aimed to apply a thief sampling method along with reliable NIR spectroscopy to determine the endpoint of the mixture containing a low concentration of the API. The sample was taken by a thief and then scanned NIR spectrum. The calibration model was built by PLS regression based on non-treated or pre-treated spectral data. Chemometric parameters were determined. The accuracy and precision of the model were assessed by internal and independent trials for validation. The measured and the predicted results were International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 12, Issue 6, 2020