Acessibilidade / Reportar erro

A feasible classification method of wet masses to predict pellet formation of powdered herbal slices

Abstract

The aim of the current study was to explore the correlation between physical properties of wet masses and pellet quality by using powdered herbal slices as model drugs. Wet masses with 100 formulations were prepared by taking 20 kinds of powdered herbal slices as model drugs, microcrystalline cellulose as pelletization aid and five levels of added water as liquid binder. Physical properties of the wet masses such as hardness, adhesiveness, springiness, cohesiveness, chewiness, and resilience were measured by a texture analyzer. Meanwhile, the moisture retention capacities (MRC) of powdered herbal slices and wet masses were determined. Particles were classified after they were produced during spheronization. Principal component analysis, factor analysis and classification analysis were performed on the data. Wet masses could be classified into three groups by taking Ha as the first classification index and Ha/Sp as the second classification index. The correct rate of the classification was 91.00%. If Ha value of wet masses was greater than 15610 g, pellets of type ① would form, otherwise, pellets of type ② or type ③ would form based on Ha/Sp value. Then a classification plot of wet masses was developed to predict pellet formation of powdered herbal slices. Meanwhile, the probable mechanism of pellets formation during spheronisation was concluded in this study, which provided useful information to improve pellet quality.

Keywords:
Extrusion-spheronization; Physical properties; Wet mass; Powdered herbal slices; Principal component analysis


INTRODUCTION

Extrusion-spheronization, first suggested by by Reynolds (1970)Reynolds AD. A new technique for the production of spherical particles. Manuf. Chem. Aerosol New. 1970;41:40-43. and Conie (1970)Conine JW, Hadley HR. Preparation of small solid pharmaceutical spheres. Drug Cosmet Ind. 1970;106:38. is a multi-step mechanical process (Zolkefpeli, Wong, 2013Zolkefpeli SNM, Wong TW. Design of microcrystalline cellulose-free alginate spheroids by extrusion-spheronization technique. Chem Eng Res Des. 2013;91(12):2437-2446.) widely used in the pharmaceutical industry for manufacturing pellets (Lau et al., 2014Lau CLS, Yu Q, Lister VY, Rough SL, Wilson DI, Zhang, M. The evolution of pellet size and shape during spheronisation of an extruded microcrystalline cellulose paste. Chem Eng Res Des. 2014;92(11):2413-2424.). By a series of unit operations including dry blending, wet-massing, extrusion, spheronzation and drying (Krueger et al., 2013Krueger C, Thommes M, Kleinebudde P. Spheronisation mechanism of MCC II-based pellets. Powder Technol. 2013;238:176-187.; Ghebre-Sellassie, Martin, 2003Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. Marcel Dekker, New York, Basel. 2003.), pellets with a narrow size distribution and a low friability were prepared (Dukic-Ott et al., 2009Dukic-Ott A, Thommes M, Remon JP, Kleinebudde P, Vervaet C. Production of pellets via extrusion-spheronisation without the incorporation of microcrystalline cellulose: A critical review. Eur J Pharm Biopharm. 2009;71(1):38-46.). Nowadays, pellets, as a kind of multiparticulate oral solid dosage form with a main advantage of high drug loading have drawn much attention (Chamsai, Sriamornsak, 2013Chamsai B, Sriamornsak P. Novel disintegrating microcrystalline cellulose pellets with improved drug dissolution performance. Powder Technol. 2013;233:278-285.).

The mechanisms about extrusion-spheronization have been discussed continuously. In 1985, a mechanism about extrusion-spheronization was proposed that the extrudates underwent the stages of forming cylinders with equal lengths, cylinders with round edges, dumbbell shaped particles and elliptical particles, finally resulting in spheres (Rowe, 1985Rowe RC. Spheronization: a novel pill-making process. Int J Pharm. 1985;6:119-123.). Baert et al. (1993)Baert L, Vermeersch H, Remon JP, Smeyers-Verbeke J, Massart DL. Study of parameters important in the spheronisation process. Int J Pharm. 1993; 96:225-229. extended the mechanism by advancing a theory that the dumb-bell shaped particles would break into two spheres with cavities outside in the spheronization process (Vervaet et al., 1995Vervaet C, Baert L, Remon JP. Extrusion-spheronisation: A literature review. Int J Pharm. 1995;116(2):131-146.). A new mechanism was raised that the cyclindrical extrudates went through three stages of becoming cylinders with rounded edges and fractured fines, dumb-bell shaped particles with agglomerated fines and elliptical particles by deformation and agglomeration among particles (Liew et al., 2007Liew CV, Chua SM, Heng PWS. Elucidation of spheroid formation with and without the extrusion step. AAPS PharmSciTech. 2007;8(1):1-10.) and finally were spheronized into spheres (Koester et al., 2012Koester M, Willemsen E, Krueger C, Thommes M. Systematic evaluations regarding interparticular mass transfer in spheronization. Int J Pharm. 2012;431(1-2):84-89.). Koester and Thommes (2010)Koester M, Thommes M. New insights into the pelletization mechanism by extrusion/spheronization. AAPS PharmSciTeCh. 2010;11(4):1549-1551. and Bryan et al. (2015)Bryan MP, Atherton LN, Duffield S, Rough SL, Wilson DI. Stages in spheronisation: Evolution of pellet size and shape during spheronisation of microcrystalline cellulose-based paste extrudates. Powder Technol. 2015;270(Part A):163-175. summarized these mechanisms, respectively. Previous study of our team (Gao et al., 2013Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.) investigated the relationship between the physical properties of wet masses and the different shapes of the obtained particles after spheronization. The results showed that the wet masses need a suitable range of hardness (Ha) and chewiness (Ch), which will help them first break into short cylinders and then form the short cylinder into an intermediate shape with rounded edges, eventually forming spherical particles due to suitable elasticity (Sp), resilience (Re), cohesion (Co) and small adhesion (Ad).

Texture analysis (TA) is commonly used to investigate the mechanical response of solids and liquids in the food and cosmetic industry (Estellé et al., 2006Estellé P, Lanos C, Mélinge Y, Servais C. On the optimisation of a texture analyser in squeeze flow geometry. Measurement. 2006;39(8):771-777.), such as the texture measurement of fruit (Giongo et al., 2013Giongo L, Poncetta P, Loretti P, Costa F. Texture profiling of blueberries (Vaccinium spp.) during fruit development, ripening and storage. Postharvest Biol Technol. 2013;76:3439.) and meat products (Martinez et al., 2004Martinez O, Salmerón J, Guillén MD, Casas C. Texture profile analysis of meat products treated with commercial liquid smoke flavourings. Food Control. 2004;15(6);457-461.; Ávila et al., 2014Ávila MDR, Cambero MI, Ordóñez JA, Hoz L, Herrero AM. Rheological behaviour of commercial cooked meat products evaluated by tensile test and texture profile analysis (TPA). Meat Sci. 2014;98(2):310-315.). Nowadays, it has been applied to the chemical (Nalesso et al., 2015Nalesso S, Codemo C, Franceschinis E, Realdon N, Artoni R, Santomaso AC. Texture analysis as a tool to study the kinetics of wet agglomeration processes. Int J Pharm. 2015;485(12):61-69.) and pharmaceutical industry (Mércia, Suzana caetano, 2007Mércia FE, Suzana caetano SL. Use of texture analysis to determine compaction force of powders. J Food Eng. 2007;80(2):568-572.). By the wet mass analysis, the physical properties of wet masses (Gao et al., 2013Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.) can be characterized, such as Ha, Sp, Co, Ch, Ad and Re (Bourne, 1978Bourne MC. Texture profile analysis. Food Technol. 1978;32:62-66.; Singh et al., 2013Singh V, Guizani N, Al-Alawi A, Claereboudt M, Rahman MS. Instrumental texture profile analysis (TPA) of data fruits as a function of its physico-chemical properties. Ind Crops Prod. 2013;50:866-873.).

Traditional Chinese medicine (TCM) has been used in China for thousands of years to treat people with poor health (Bian et al., 2012Bian ZX, Chen SL, Cheng CW, Wang J, Xiao HT, Qin HY. Developing new drugs from annals of Chinese medicine. Acta Pharm Sin B. 2012;2(1):1-7.). TCM preparations commonly used are generally made of the extract of herbal slices to reduce the daily dose (Pretoro et al., 2010Pretoro GD, Zema L, Gazzaniga A, Rough SL, Wilson DI. Extrusion-spheronisation of highly loaded 5-ASA multiparticulate dosage forms. Int J Pharm. 2010;402(12):153-164.). However, TCM preparations made directly from powdered herbal slices account for 27% in Chinese Pharmacopoeia 2015 edition (National Pharmacopoeia Committee, 2015National Pharmacopoeia Committee. Pharmacopoeia of People’s Republic of China, Part 1. 2015;Beijing: Chemical Industry Press: Appendix 181-182.). Some herbal slices are usually ruled to be directly made into preparations because they have better clinical effect than extracts (Li, 2009Li YL. Pharmaceutics of TCM. Higher Education Press, China. 2009.; Zou et al., 2015Zou BL, Zhang GD, Gu SP, Wang JN, Wang YQ, Shao X, Yu HH, Yu RH, Zhou CY. Clinical observation on decoction and powder of xiaoyao powder formula in the treatment of liver stagnation and spleen deficiency. J Tradit Chin Med. 2015;56(3):216-218.). On one hand, some aromatic traditional Chinese drugs can avoid the volatilization of the active ingredients. One the other hand, some precious medicinal materials such as Sanqi (Notoginseng Radix Et Rhizoma) could reduce the loss of drugs and save the resources. The last but not the least, the main active ingredients are insoluble in water in many animal medical slices containing protein and protein hydrolytic products (Liu et al., 2015Liu QH, Wen J, Peng ZP, Liu FL, Tong XL. Review of the powder and decoction formulae in Traditional Chinese Medicine based on pharmacologically active substances and clinical evidence. J Tradit Chin Med. 2015;35(3):355-360.). Therefore, it’s quite necessary to study the process and the concept of pellet formation when using powdered herbal slices as model drugs. Our previous work (Gao et al., 2013Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.) gave much information on wet masses and pellet quality assessment in extrusion-spheronization process by taking microcrystalline cellulose as pelletization aid and lactose, hydroxypropyl methylcellulose grades, powdered herbal extracts as model drugs with different drug loadings. A structured protocol for the classification of wet mass was developed to predict the formation and quality of the pellets. However, it is still unclear whether the protocol can be applied to the process when using powdered herb as model drugs.

The aim of the current work was to explore the effect of the physical properties of wet mass on pellet formation and to develop a protocol to predict pellet quality by using powdered herbs as model drugs.

MATERIAL AND METHODS

Material

Microcrystalline cellulose (MCC, lot number F06010004) with a mean particle size of 50 μm used as the excipient, was obtained from Anhui Sunhe Pharmaceutical Excipients Co., Ltd, China. 20 kinds of Traditional Chinese herbal slices were purchased from Shanghai Cambridge Chinese Herbal Slices Co., Ltd, China. The herbal slices were as follows: Citri Reticulatae Pericarpium (Chen Pi, CRP, lot number 150314), Aurantii Fructus (Zhi Ke, AF, lot number 150112), Paeoniae Radix Alba (Bai Shao, PRA, lot number 150319), Chrysanthemi Flos (Ju Hua, CF, lot number 150225), Moutan Cortex (Mu Danpi, MC, lot number 150226), Chaenomelis Fructus (Mu Gua, CHF, lot number 141225), Astragali Radix (Huang Qi, AR, lot number 150321), Zingiberis Rhizoma (Gan Jiang, ZR, lot number 150321), Glycyrrhizae Radix Et Rhizoma (Gan Cao, GRER, lot number 150323), Dioscoreae Rhizoma (Shan Yao, DR, lot number 150320), Angelicae Sinensis Radix (Dang Gui, ASR, lot number 150314), Ligustri Lucidi Fructus (Nv Zhenzi, LLF, lot number 150104), Eriobotryae Folium (Pi Paye, FE, lot number 150312), Puerariae Lobatae Radix (Ge Gen, PLR, lot number 151005), Uncariae Ramulus Cum Uncis (Gou Teng, URCU, lot number 151008), Inulae Flos (Xuan Fuhua, IF, lot number 150928), Rehmanniae Radix (Di Huang, RR, lot number HP2015120603), Plantaginis Semen (Che Qianzi, PS, lot number XD2015122201), Curcumae Rhizoma (E Zhu, CR, lot number 2015041302), Ophiopogonis Radix (Mai Dong, OR, lot number HP2015051601). CRP, AF, CHF and LLF are from the fruit of herbs, PRA, MC, AR, ASR, PLR, RR and OR from the root of herbs, CF and IF from the flower of herbs, ZR, DR, URCU and CR from the stem of herbs, EF from the leaf, PS from the seed and GRER from both root and stem. Ultrapure water which was used as the moistening liquid and liquid binder, was generated by Millipore Direct-Q3 system.

Dry milling

Powdered herbal slices were prepared by a DFT250 electric milling machine (Shanghai, China). After repeated milling and sieving through an 80 mesh sieve, the powdered model drugs were obtained (Kumar, Burgess, 2014Kumar S, Burgess DJ. Wet milling induced physical and chemical instabilities of naproxen nano-crystalline suspensions. Int J Pharm. 2014;466(1-2):223-232.).

The size and size distribution of powdered herbal slices

The sizes of the powdered herbal slices were determined by a Mastersizer 2000 particle size analyzer (Malvern, Worcestershire, UK) fitted with a dry powder feeder and laser beam. The size distribution, defined as span, was calculated as follows:

Span =d90-d10d50
where d90, d50 and d10 represented the corresponding 90th, 50th and 10th percentiles of the accumulative particle size distribution, respectively.

True density measurement of powdered herbal slices

An AccuPyc Pycnometer (AccuPyc II 1340 V1.05 Unit1 Serial No. 949) was employed for the true density measurement of powdered herbal slices with helium as analysis gas.

Extrusion-spheronization process

MCC, 20 kinds of model drugs and five levels of water were used in the study. 200 g of MCC-drug mixture powder loaded with 30% w/w drug was added into a container and was diluted by geometry for 5 min. Water was added by spraying onto the powder blends.

The mixing and wetting processes were completed within 10 min. The amount of water added which was calculated as a percentage of the total mixture weight, was set at different levels to form different types of particle. Wet masses were extruded with a rotating speed of 60 r/min through a single axial screw extruder (E50, Chongqing Eagle Pharmaceutical Machinery Co, Ltd, Chongqing, China) fitted with a screen of 0.6 mm aperture diameter, 1 mm thickness and 15 aperture per inch, to produce extrudates.

100 g of extrudates were subsequently spheronized at 1200 r/min for 3 min using a spheronizer (S-250, Chongqing Eagle Pharmaceutical Machinery Co., Ltd., Chongqing, China) fitted with a friction plate of 250 mm diameter. Then the prepared particles were dried in an oven at 40 ºC for 3 h.

Texture measurement of wet masses

As there was little difference in the physical properties between wet masses and extrudates for the same formulation, the physical properties of the extrudates were measured by texture profile analysis (TPA). A texture analyzer TA-XT plus (Stable Micro System Ltd., UK) was used with an acrylic cylindrical cup of 55 mm in diameter as a sample container and an aluminum back extrusion probe A/B E connecting to a disk with a diameter of 45 mm. TPA was performed at room temperature and the parameters were set based on the study conducted by Ya Gao (Gao et al., 2013Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.). 30 g of extrudates in the sample container were axially compressed to 40% of the original height using a twocycle compression test with 5 s allowed to elaspe between the two compression cycles (Zheng et al., 2015Zheng HB, Xiong GY, Han MY, Deng SL, Xu XL, Zhou GH. High pressure/thermal combinations on texture and water holding capacity of chicken batters. Innovative Food Sci. Emerging Technol. 2015;30:8-14.). The trigger force was 1500 g, with a pre-test speed of 2 mm/s, test speed of 5 mm/s and post-test speed of 5 mm/s. Each sample was determined in three replicates by Exponent software (Exponent Stable Microsystem, version 6.1.7.0, Stable Microsystems Ltd., UK) and the results were averaged. The parameters Ha, Sp, Co, Ch, Ad and Re were acquired. Both extrusion-spheronization process and texture measurement of the same formulation were conducted on the same day in order to reduce error.

Categorization of pellets

Particles produced by extrusion and spheronization after drying in the oven were sieved using a 60 mesh sieve to separate the fine particle fraction. Then the particles were divided into three categories according to the morphology of 50 randomly selected particles. The particles were divided into one type when the number was over 25. Type ①: clavate pellets, double sphere or dumb-bell shaped pellets; type ②: spherical pellets; type ③: oversized pellets (size > 0.2 mm).

The measurement of moisture retention capacity (MRC)

MRC is the ability of the materials to hold water when subjected to a certain force, which may finally influence the physical properties of wet masses (Tomer et al., 2001Tomer G, Patel H, Podczeck F, Newton JM. Measuring the water retention capacities (MRC) of different microcrystalline cellulose grades. Eur J Pharm Sci. 2001;12(3):321-325.). Therefore, the MRC was conducted in this study for the water retention measurement of powdered herbal slices (Gao et al., 2013Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.) and wet masses (Tomer, Newton, 1999Tomer G, Newton JM. A centrifuge technique for the evaluation of the extent of water movement in wet powder masses. Int J Pharm. 1999;188(1):31-38.).

MRC measurement of powdered herbal slices

MRC of powdered herbal slices (MRCP) was measured using a 10.0 mL of centrifuge tube. 0.5 g of herbal slice powder sample was deposited into a 10.0 mL of centrifuge tube and 5 mL of ultrapure water was added to make powder uniformly suspended in water by vibrating the tube for 2 min. After keeping the suspension static for 10 min, the tube was vibrated for 2 min and centrifuged at 3000 r/min for 15 min. The supernatant liquid was then poured out. The MRCP was measured by the following equation according to the percentage of residual water precipitated in the tube. The blank centrifuge tube was weighed as W1 and centrifuge tube with precipitate was weighed as W2.

MRCP=W2-W10.5×100%

MRC of wet masses

MRC of wet masses (MRCw) was measured using a 2.0 mL-centrifuge tube with an ultrafiltration centrifuge tube (Figure 1). Extrudates used to replace wet masses were cut into cylinders (5 mm in length and 1 mm in diameter). Then 0.3 g of the cylinders were put into the tube to be centrifuged at 5500 r/min for 30 min. Water contents of wet masses before and after centrifuge were Wpre and Wpost, respectively. Wwater was the added water content during the wet mass preparation process. The blank ultrafiltration centrifuge tube and the tube after centrifuge were weighed as W1 and W2, respectively.

MRCw=Wpost Wpre ×100%=Wpre -(W2-W1)Wpre ×100%,Wpre =0.3Wwater 100+Wwater 

FIGURE 1
The schematic diagram of ultrafiltration centrifuge tube.

Data analysis

The Uncrambler (V9.7, Camo Software, Oslo, Norway) was employed for the analysis of physical properties of wet mass and the particle types. The data could be simplified by producing a new set of principal components and retaining the minimum loss of information (Jolliffe, 2002Jolliffe IT. Principal Component Analysis, second edition, Springer. 2002.).

The physical properties of wet masses and pellet types were classified through Waikato Environment for Knowledge Analysis (WEKA, V3.7.13, the University of Waikato Hamilton, New Zealand).

The physical properties of wet masses were correlated to those of the wet masses using Pearson’s correlation analysis (SPSS Version 18.0 for Windows, SPSS Inc., IL, USA).

RESULTS AND DISCUSSION

The size distribution and true density results of 20 kinds of powdered herbal slices

The size distribution and true density results of 20 kinds of powdered herbal slices were shown in Table I, which indicated that after dry milling and through 80 mesh, the size, size distribution and true density of 20 kinds of powdered herbal slices were in the range of 70.27 ~ 80.54 μm, 2.14 ~ 2.87 and 1.50 ~ 1.55 g/cm3, respectively, with no significant difference.

TABLE I
The size and size distribution, true density and MRC of powdered herbal slices (n=3, x¯±s)

The size and size distribution, true density and MRC of powdered herbal slices (n=3, x¯±s)

Characterization of wet masses and pellets

The physical property data of the wet masses and the categories of pellets from 100 formulations were presented in Table II. The physical properties of different kinds of wet masses with five levels of water additon were quite different and the shapes of the obtained particles are also of different types. Compared with the physical properties of the wet masses which use lactose, hydroxypropyl methylcellulose grades, powdered herbal extracts as model drugs (Gao et al., 2013Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.), the Ha and Ch values in this work were significantly reduced. The possible reason was that there were many fibers in the wet masses when taking powdered herbal slices as model drugs and the longer fibers were not well compacted. So the wet masses were less dense, resulting in smaller values of Ha and Ch. It was also found that the Ad values were in a low level as they were less stick than the powdered herbal extract when wetted by water.

TABLE II
The physical properties of wet masses and categories of pellets from 100 formulations (n=3, x¯±s)

According to Table III, significant correlations were found between MRCw and the six physical properties of wet masses, except the correlation between Sp and Re. In addition, the correlations were all positive except the correlation between Sp and other physical properties. Meanwhile, the Ha, Ad, Sp, Co, Ch and Re values of 20 kinds of powdered herbal slices were plotted in Figure 2. The results revealed that the increase of added water ratio was accompanied by a significant decrease of the Ha, Ad, Co, Ch, Re values and a significant increase of the Sp value, apart from few data.

The physical property data of wet masses were averaged and standardized, and then a radar chart was plotted (Figure 3). The chart indicated that different types of pellets possessed different shapes because of different physical properties of wet masses. For example, wet masses for pellets of type ① had bigger Co, Ch, Ha, Re and smaller Sp values, but wet masses for pellets of type ③ had bigger Sp and smaller Ha, Ad, Ch, Co values. If good pellets were obtained, the wet masses should have medium values of physical properties.

MRC data of powdered herbal slices and wet masses were shown in Table I, Table II and Figure 4, respectively. For the 20 kinds of powdered herbal slices, MRCp of AR and EF were in the lowest and highest location, respectively. MRCw of wet masses from 20 kinds of powdered herbal slices decreased with increasing water ratio. Pearson’s correlation analysis (Table III) showed that MRCw was correlated with Ha, Ad, Sp, Co, Ch and Re of wet masses. Therefore, MRCw data of wet masses were regarded as one of physical properties in the classification analysis of wet masses.

FIGURE 2
The six physical properties plot of wet masses from 20 kinds of powdered herbal slices (A. Hardness; B. Adhesiveness; C. Springiness; D. Cohesiveness; E. Chewiness; F. Resilience).
FIGURE 3
Radar chart of the physical properties of wet masses for three types of particles.
FIGURE 4
MRC plots of powdered herbal slices (a) and wet masses (b) from 20 kinds of TCM.
TABLE III
Pearson’s correlation analysis result among MRCw and the six physical properties of wet masses

Classification of wet masses

The physical property data of wet masses in Table II were analyzed by using principal component analysis (PCA) in order to classify the wet masses. PCA scores plot (Figure 5A) showed that the first two principals could generally divide the 100 formulations into three parts, which explained 68% and 16% of the physical properties, respectively. Meanwhile, PCA result made by SPSS demonstrated the λ value corresponding to the first two principal components had taken up a cumulative percentage of 83.54% and the λ of the first PCs was 4.053 shown in Table IV. λ was the eigenvalues in PC analysis, representing the variance of PCA scores, and when λ value is more than 1, the corresponding PCs would be retained. Therefore, PC1 proves to be more important than PC2. Compared with Sp, Ha, Ad, Co, Ch and Re were in the opposite directions in the first principal component (Figure 5B). Ha and Sp might be the more valuable parameters if the results of PC1 and PC2 were taken into account simultaneously. Ten-fold crossvalidation method was used for further classification analysis with the averaged physical properties of wet masses as input variable and categories of particles as output variable. A J48 pruned tree of wet masses classification with 91% correctly classified formulations was obtained. According to the result, the wet masses could be classified into 3 groups by taking Ha as the first classification index, Ha/Sp as the second classification index, respectively. It seemed that other physical parameters didn’t contribute to the classification of wet masses, including MRC. If Ha value of wet masses was more than 15610 g, it would form pellets of type ①. If Ha value was no more than 15610 g, it would form pellets of type ② or type ③ based on Ha/Sp value; type ① was produced when Ha/Sp value was over 18843, and type ③ was formed when Ha/Sp value was less than 18843. Therefore a very simple classification plot of wet masses was obtained which used to predict the types of particles under the drug loading of 30% (Figure 6A).

If Ha/Sp was taken subjectively as the first classification index and Ha as the second one, another simple classification plot of wet masses was gained (Figure 6B). And there were still 9 formulations incorrectly classified. Therefore, it could be concluded that Ha/Sp and Ha play an equally important role in the spheronization process. Other physical properties such as Ad, Ch, Co, Re and MRC had no contribution to the classification plot and could not enhance the classification accuracy.

Therefore, the functions of physical properties of wet mass could be concluded in spheronization process when the mechanisms of pellets formation (Figure 7) were argued. The cylindric wet masses would be cut by the shear plate and were not prone to produce deformation due to their higher hardness. Clavate, double sphere or dumbbell shaped pellets were produced because of the difficulty in cutting of cylindric wet masses. So a smaller Ha value would benefit the cutting process. Particles are tumbled, collided, and rotated in the spheronization process, and are shaped by mechanical forces such as centrifugal force, friction force, elastic force and so on. With the decrease of Ha, particles become soft and easy to deform, and then they are combined together under the mechanical forces in the spheronization process. Another case was that particles became easily recovered with the increasing Sp, and then embedded in each other. Finally, oversized pellets were obtained. Therefore the wet masses require a proper range of Ha, which would help them to be initially broken up into short cylinders, and formed the short cylinder into an intermediate shape with round edges and finally, forming spherical pellets as a result of a suitable Sp.

FIGURE 5
(A) PCA score plot of the physical properties of wet masses for type ① (⃝), type ② (⃝) and type ③(⃝). (B) PCA loading plot of the physical properties of wet masses.
FIGURE 6
classification plot of wet mass used to predict the type of pellets, taking Ha (a) and Ha/Sp (b) as the first classification index, respectively.
FIGURE 7
The probable formation mechanisms of pellets in spheronization process(a) clavate, double sphere or dumb-bell shaped pellets; (b) spherical pellets;(c) oversized pellets.
TABLE IV
PCA result of the physical properties of wet masses

CONCLUSIONS

In this study, a classification plot of wet masses which was used to predict pellet types for powdered herbal slices with 30% drug loading is exhibited. Taking Ha as the first classification index, Ha/Sp as the second, the wet masses could be classified into three types. Therefore, the quality of the final product can be predicted in accordance with their physical properties. Meanwhile, the functions of physical properties of wet mass were concluded in spheronization process when the mechanisms of pellets formation were argued, which may provide useful information to improve pellet quality.

ACKNOWLEDGEMENTS

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81202923) and Suzhou Scientific and Technological Projects of People’s Livelihood (Grant No. SYSD2018072).

REFERENCES

  • Ávila MDR, Cambero MI, Ordóñez JA, Hoz L, Herrero AM. Rheological behaviour of commercial cooked meat products evaluated by tensile test and texture profile analysis (TPA). Meat Sci. 2014;98(2):310-315.
  • Baert L, Vermeersch H, Remon JP, Smeyers-Verbeke J, Massart DL. Study of parameters important in the spheronisation process. Int J Pharm. 1993; 96:225-229.
  • Bian ZX, Chen SL, Cheng CW, Wang J, Xiao HT, Qin HY. Developing new drugs from annals of Chinese medicine. Acta Pharm Sin B. 2012;2(1):1-7.
  • Bourne MC. Texture profile analysis. Food Technol. 1978;32:62-66.
  • Bryan MP, Atherton LN, Duffield S, Rough SL, Wilson DI. Stages in spheronisation: Evolution of pellet size and shape during spheronisation of microcrystalline cellulose-based paste extrudates. Powder Technol. 2015;270(Part A):163-175.
  • Chamsai B, Sriamornsak P. Novel disintegrating microcrystalline cellulose pellets with improved drug dissolution performance. Powder Technol. 2013;233:278-285.
  • Conine JW, Hadley HR. Preparation of small solid pharmaceutical spheres. Drug Cosmet Ind. 1970;106:38.
  • Dukic-Ott A, Thommes M, Remon JP, Kleinebudde P, Vervaet C. Production of pellets via extrusion-spheronisation without the incorporation of microcrystalline cellulose: A critical review. Eur J Pharm Biopharm. 2009;71(1):38-46.
  • Estellé P, Lanos C, Mélinge Y, Servais C. On the optimisation of a texture analyser in squeeze flow geometry. Measurement. 2006;39(8):771-777.
  • Gao Y, Hong YL, Xian JC, Lin X, Shen L, Zhang X, Zhang N, Feng Y. A protocol for the classification of wet mass in extrusion-spheronization. Eur J Pharm Biopharm. 2013;85(3):996-1005.
  • Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. Marcel Dekker, New York, Basel. 2003.
  • Giongo L, Poncetta P, Loretti P, Costa F. Texture profiling of blueberries (Vaccinium spp.) during fruit development, ripening and storage. Postharvest Biol Technol. 2013;76:3439.
  • Jolliffe IT. Principal Component Analysis, second edition, Springer. 2002.
  • Koester M, Thommes M. New insights into the pelletization mechanism by extrusion/spheronization. AAPS PharmSciTeCh. 2010;11(4):1549-1551.
  • Koester M, Willemsen E, Krueger C, Thommes M. Systematic evaluations regarding interparticular mass transfer in spheronization. Int J Pharm. 2012;431(1-2):84-89.
  • Krueger C, Thommes M, Kleinebudde P. Spheronisation mechanism of MCC II-based pellets. Powder Technol. 2013;238:176-187.
  • Kumar S, Burgess DJ. Wet milling induced physical and chemical instabilities of naproxen nano-crystalline suspensions. Int J Pharm. 2014;466(1-2):223-232.
  • Lau CLS, Yu Q, Lister VY, Rough SL, Wilson DI, Zhang, M. The evolution of pellet size and shape during spheronisation of an extruded microcrystalline cellulose paste. Chem Eng Res Des. 2014;92(11):2413-2424.
  • Li YL. Pharmaceutics of TCM. Higher Education Press, China. 2009.
  • Liew CV, Chua SM, Heng PWS. Elucidation of spheroid formation with and without the extrusion step. AAPS PharmSciTech. 2007;8(1):1-10.
  • Liu QH, Wen J, Peng ZP, Liu FL, Tong XL. Review of the powder and decoction formulae in Traditional Chinese Medicine based on pharmacologically active substances and clinical evidence. J Tradit Chin Med. 2015;35(3):355-360.
  • Martinez O, Salmerón J, Guillén MD, Casas C. Texture profile analysis of meat products treated with commercial liquid smoke flavourings. Food Control. 2004;15(6);457-461.
  • Mércia FE, Suzana caetano SL. Use of texture analysis to determine compaction force of powders. J Food Eng. 2007;80(2):568-572.
  • Nalesso S, Codemo C, Franceschinis E, Realdon N, Artoni R, Santomaso AC. Texture analysis as a tool to study the kinetics of wet agglomeration processes. Int J Pharm. 2015;485(12):61-69.
  • National Pharmacopoeia Committee. Pharmacopoeia of People’s Republic of China, Part 1. 2015;Beijing: Chemical Industry Press: Appendix 181-182.
  • Pretoro GD, Zema L, Gazzaniga A, Rough SL, Wilson DI. Extrusion-spheronisation of highly loaded 5-ASA multiparticulate dosage forms. Int J Pharm. 2010;402(12):153-164.
  • Reynolds AD. A new technique for the production of spherical particles. Manuf. Chem. Aerosol New. 1970;41:40-43.
  • Rowe RC. Spheronization: a novel pill-making process. Int J Pharm. 1985;6:119-123.
  • Singh V, Guizani N, Al-Alawi A, Claereboudt M, Rahman MS. Instrumental texture profile analysis (TPA) of data fruits as a function of its physico-chemical properties. Ind Crops Prod. 2013;50:866-873.
  • Tomer G, Newton JM. A centrifuge technique for the evaluation of the extent of water movement in wet powder masses. Int J Pharm. 1999;188(1):31-38.
  • Tomer G, Patel H, Podczeck F, Newton JM. Measuring the water retention capacities (MRC) of different microcrystalline cellulose grades. Eur J Pharm Sci. 2001;12(3):321-325.
  • Vervaet C, Baert L, Remon JP. Extrusion-spheronisation: A literature review. Int J Pharm. 1995;116(2):131-146.
  • Zheng HB, Xiong GY, Han MY, Deng SL, Xu XL, Zhou GH. High pressure/thermal combinations on texture and water holding capacity of chicken batters. Innovative Food Sci. Emerging Technol. 2015;30:8-14.
  • Zolkefpeli SNM, Wong TW. Design of microcrystalline cellulose-free alginate spheroids by extrusion-spheronization technique. Chem Eng Res Des. 2013;91(12):2437-2446.
  • Zou BL, Zhang GD, Gu SP, Wang JN, Wang YQ, Shao X, Yu HH, Yu RH, Zhou CY. Clinical observation on decoction and powder of xiaoyao powder formula in the treatment of liver stagnation and spleen deficiency. J Tradit Chin Med. 2015;56(3):216-218.

Publication Dates

  • Publication in this collection
    26 Nov 2021
  • Date of issue
    2021

History

  • Received
    19 Dec 2018
  • Accepted
    27 Aug 2019
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br