Real-time droplet size analysis using laser micrometer as a process analytical technology tool for continuous dripping process

Process analysis and monitoring during the manufacturing of the dripping pills are essential. However, research on developing sensor-based technology or process analytical technology (PAT) tools to analyze and monitor the dripping process is minimal. The purpose of this work is to develop a fast and non-destructive laser detection system for quantitative visualization of droplets, which involves detecting the size of the droplet and calculating the weight of the dripping pills during the dripping process. Several factors influencing the detection performance of the detection system and the detection system capability for quantitation of the pill weight were explored. The laser detection system accurately detects the weight of the dripping pills with the coefficients of determination (R²) higher than 0.99. It was also robust concerning the variation in critical process parameters and critical material attributes. Furthermore, the laser detection system was successfully applied to the production line of Ginkgo biloba leaf dripping pills to monitor the dripping pills weight. The proposed laser detection system can analyze and monitor the dripping process in dripping pill manufacturing with stable performance, high accuracy, and high efficiency.

Introduction

With the rapid development of information technology (IT) and artificial intelligence (AI), intelligent manufacturing and industry 4.0 manufacturing have become the research focus in many industries [1-4]. The pharmaceutical industry is also on the way to realizing intelligent manufacturing and fostering innovations. The advances in sensor technology, data analytics, and system modeling were described as important innovations to understand, design, and control complex manufacturing processes [5]. The application of various sensors plays an important role in supporting advanced process-control strategies and automated operation in pharmaceutical manufacturing.

Moreover, PAT was introduced by the US Food and Drug Administration (USFDA) and defined as “a system that designs, analyzes, and controls manufacturing by measuring the critical attributes of materials and critical process parameters during the production process, to ensure final product quality” [6, 7]. Accurate on-line measurements of critical process parameters are vital for successful monitoring and process control. Therefore, PAT tools also play a crucial role in pharmaceutical manufacturing [8-10].

The dripping pill is a pharmaceutical oral solid dosage form that can be prepared using solid dispersion technology [11-13]. In recent years, dripping pills have been extensively used for clinical applications due to their excellent bioavailability and pharmacokinetics [14, 15]. The preparation process of dripping pills usually consists of five steps, that is, hot melting, dripping, condensing, washing, and coating [16]. After the hot melting process, the well-blended molten mixture flows out from the drop head as droplets. Then, the droplets fall into the condensing column and are solidified by cold oil to form spherical pills. The pill weight is a critical quality attribute of the dripping pill products which depends on the droplet size. The variation of the pill weight will seriously influence the dosage, and it is a common and important indicator reflecting the size uniformity of dripping pills. Accordingly, the pill weight must be precisely controlled to ensure the quality of dripping pills. The pill weight is influenced by many process parameters, such as the temperature of the dispersing liquid, the drop speed, the drop distance, the temperature of the condensing liquid and so on. In industrial production lines, operators usually sample droplets from a drop head every ten minutes or half an hour and weigh them using an electronic balance to monitor the dripping process. However, there are few studies of sensor technology or PAT tools that can inspect the quality of the dripping pills [17], monitor and control the dripping process [18]. Therefore, more efficient detection systems should be constructed based on sensor technology or PAT tools to better understand, analyze, monitor, and control the preparation process in dripping pills manufacturing.

Practical Application

The laser detection technique is a nondestructive measuring tool based on the theory of laser diffraction or charge-coupled device (CCD) light projection. Laser detection techniques have been used in many industries, such as on-line detection of particle size in pharmaceuticals [19-22], production and detection of parts in manufacturing [23-26], and material determination in medicine [27]. Considering laser detection technique and its wider applications, the present study was conducted to develop an on-line analysis and monitoring system based on a high-detection sensitivity CCD laser micrometer for the quantitative visualization of droplets during the dripping process. As a traditional herbal drug stipulated in the Pharmacopeia of the People’s Republic of China [16], Ginkgo biloba leaf dripping pills was studied as an example. We analyzed and monitored the dripping process of Ginkgo biloba leaf dripping pills by using the proposed laser detection system. The widths of the droplet in the dripping process were captured and used to further calculate the size of the droplet. Furthermore, a quantitative relation was established between the size of droplets and the weight of the dripping pills. The proposed method provides a novel PAT for on-line analysis and monitoring the dripping process of dripping pills.

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Xiaoping Wang: Conceptualization, Methodology, Software, Investigation, Formal analysis, Writing- Original draft preparation, Writing- Review and Editing. Ying Tian: Investigation, Validation. Sheng Zhang: Formal analysis, Validation. Haibin Qu: Supervision, Conceptualization, Writing- Review and Editing, Funding acquisition.
https://doi.org/10.1002/elsc.202200024