Application of hydroxypropyl methylcellulose in surface modification of traditional Chinese medicine powder in direct compression process

Abstract: Compared with the tableting process after granulation, the direct compression process is the best choice for tablet production. However, due to its high performance requirements for raw materials, only a small amount of drugs can be produced by the direct compression process. . Based on the principles of particle engineering, most researchers select suitable modifiers and prepare composite particles by co-processing to improve the direct compression performance of powders and promote the development and production of direct compression technology. Hydroxypropyl methyl cellulose (HPMC) has many advantages. It is not only used as an excipient, but also often used as a modifier to modify the powder of traditional Chinese medicine and then used in direct compression tablet production. Therefore, this paper reviews HPMC with direct compression specifications, HPMC surface-modified composite particles, their application in direct compression of traditional Chinese medicine powder and common modification methods, in order to provide a basis for the further development and application of HPMc in direct compression of traditional Chinese medicine powder. Base.

Key words: hydroxypropyl methylcellulose; traditional Chinese medicine powder; surface modification; direct compression process

Tablets are one of the most widely used dosage forms, and the preparation processes include dry granulation, wet granulation, and direct compression. Among them, the direct compression process can simplify the production process, eliminate the adverse effects of humidity and heat, and the produced tablets are more stable, which has brought huge economic benefits to the enterprise, so it has been more and more used in related production. However, it has high requirements for powder and physical and mechanical properties of materials, such as excellent fluidity and compressibility, low hygroscopicity and lubricant sensitivity, etc. At present, only a small amount (about 20%) of drugs can be used for powder direct compression .

At present, many researchers have prepared core-shell composite particles with excellent direct compression performance through the co-processing process, which usually uses excipients with excellent direct compression performance to coat the particles (core layer) that have direct compression problems, so that the composite The direct compression performance of particles depends largely on the properties of the shell material. Hydroxypropylmethylcellulose (HPMc) has a high glass transition temperature, low hygroscopicity, optional low viscosity specification (E3), and excellent film-forming properties, and is widely used as a shell material for direct preparation. Excipients or traditional Chinese medicine composite particles with excellent compression properties. At present, HPMc of direct compression grade has been available, but there are few summaries about its application in the direct compression process of surface modification of traditional Chinese medicine powder, so this article summarizes it based on the relevant literature in the past 5 years.

1. Direct pressure grade HPMC accessories

At present, researchers have tried to develop direct pressure grade HPMc excipients. Li, Grdesic etc. mixed HPMc (K4M cR, K4M Dc, K100M cR, K100M Dc) with 1% magnesium stearate, measured the fluidity of the mixture, and found that K4M DC and K100M DC had a shorter flow time (11 .5, 12.1 s), while K4M CR and K100M CR could not be measured due to poor fluidity; the tablet weight difference RsD of tablets produced by K4M Dc and K100M Dc were 0.32% and 0.26%, which were significantly lower than Tablets produced by K4M CR and K100M CR (o.97%, 0.48%); Heckel compression equation coefficients (&) show that the four have similar compression behaviors, indicating that HPMc K4M Dc and K100M DC have better direct Compression performance, but no basic research and reports on the application of the two have been found, and there is also a lack of comparative research with other commercially available direct compression materials. At present, there are a variety of commercially available direct compression excipients (such as direct compression lactose, starch, microcrystalline cellulose, etc.). Compared with them, HPMc is better in compression molding and less hygroscopic, but it is easy to cause slow disintegration. The main reason is It is because HPMC will form a gel when it meets water, which hinders the dissolution of active ingredients.

2. HPMC surface modified direct compression excipients and its application in the direct compression process of traditional Chinese medicine powder

2.1 Binary co-processing excipients for surface modification of HPMC

Li et al. selected 3 types of 6 fillers commonly used in tablets (i.e. water-soluble small molecules, lactose, mannitol; water-insoluble small molecules, calcium carbonate, anhydrous calcium hydrogen phosphate; water-insoluble macromolecules, starch, shell polysaccharide) combined with HPMc E3, prepared co-processed excipients by spray drying method, studied the changes of powder properties and physical and mechanical properties of excipients before and after co-treatment, and used angle of repose (AR) to characterize fluidity, compression ratio (CR), Tensile strength (TS) characterizes the compressibility of the material, and the smaller the CR value, the larger the TS value, indicating better compressibility. It can be seen that, except for the combination of chitosan-HPMc, the direct compression properties of the co-processed auxiliary materials of the other combinations have been significantly improved.

It can be seen that the improvement of the direct compression performance of co-processed excipients is mainly due to the uniform distribution of HPMc with strong cohesive and plastic deformation capabilities on the surface of composite particles, and then its co-processing process is optimized to obtain fluidity and compression properties. Excellent direct pressure auxiliary material. On this basis, the mannitol-HPMC co-processing excipients were taken as an example to carry out pilot scale-up, and gardenia extract, white peony extract, Galla gall extract, Morinda officinalis extract, coix seed extract were used as models, and according to Different ratios (25:75, 50:50, 75:25) were mixed with co-processing excipients and then directly compressed to investigate its applicability in the direct compression process of traditional Chinese medicine extract powder. The study showed that the compression moldability of all Chinese herbal extracts increased with the addition of co-processed excipients, indicating that the co-processed excipients prepared in the pilot scale-up had good direct compression properties, and were comparable to commercially available direct compression excipients (mannitol-300sD) In comparison, the co-processing adjuvant presents better compressibility and greater drug loading. Under the same pressure (176 MPa) and drug loading (50%), the hardness of the tablet containing the co-processing adjuvant increased by 1 -2 times. In summary, HPMC can be used as an excellent coating material to prepare direct compression grade co-processing excipients, thereby promoting the further development of powder direct compression technology.

2.2 Ternary co-treatment auxiliary for surface modification of HPMc

Because HPMC has good plastic deformation, resulting in strong cohesion of composite particles, which is not conducive to tablet disintegration, so in addition to binary co-processing excipients, Wang et al. also explored ternary co-processing excipients to solve the problem of HPMc banding To solve the problem of slow disintegration, choose lactose with different particle sizes, and prepare lactose (core particle)-HPMc (shell layer, binder)-crospovidone (PVPP) (shell layer, disintegrant) by spray drying. In addition to Ts and cR, the yield pressure (YP) of the co-processed auxiliary materials of the element combination was also investigated. The smaller the value, the better the compressibility. Processing accessories are similar, significantly better than raw materials and equal proportion physical mixtures.

At the same time, 90 mesh lactose-10.5% HPMc-3.5% PVPP, 200 mesh lactose-7% HPMc were investigated. 3. The application of 5% PVPP combination in the direct compression tablet production of traditional Chinese medicine (gardenia extract, Galla gall extract). As a result, the tensile strength of the traditional Chinese medicine tablet increased, and the disintegration time (7.2-10 min) not only met the requirements of the 2020 edition of "Chinese Pharmacopoeia" for Chinese medicinal extract tablets (60 min), but also met the requirements of "European Pharmacopoeia" for speed. release tablet requirements (15 min).

3. HPMC surface-modified direct-pressed traditional Chinese medicine composite particles

Compared with traditional Chinese medicine, the dosage and drug loading of chemical medicine are relatively small, and the use of direct pressure grade excipients can effectively improve its direct pressure performance and make it meet the requirements of direct pressure. However, no key points have been found about HPMc as a modifier to improve chemical medicine. Research on direct pressure performance. Compared with chemical medicines, traditional Chinese medicine powders have unique physical and chemical properties, such as complex components, easy to absorb moisture and agglomerate, and mostly exist in an amorphous state, etc., and are used in larger amounts in tablet prescriptions, with less excipients, and their own direct compression properties The impact on tablet direct compression molding is also stronger than that of chemical medicine.

Most of the existing studies on the improvement of the direct compression properties of traditional Chinese medicine powders use silica as a modifier to improve their fluidity, but do not improve their compressibility. On the other hand, the research on the modification of powder by HPMc mostly focuses on excipients, and some researchers have also begun to try to apply HPMc to the research on the modification of traditional Chinese medicine powder.

Li et al. chose Andrographis paniculata extract as a model drug, mixed it with a small amount of 6% HPMc, and prepared Andrographis paniculata-HPMc composite particles through a fluidized bed bottom spray coating process. (cI), Hansohn ratio (HR), and AR characterize the fluidity of the material, and the smaller the value, the better the fluidity of the material. As a result, compared with the physical mixture of Andrographis paniculata-HPMc, the cI, HR, and AR of the corresponding composite particles decreased by 64.8%, 39.9%, and 27.8%, respectively, indicating that the modified particles have better fluidity , the main reasons are (1) the particle size of the modified particles increases, and the particle size distribution is more uniform; (2) the structure of the modified particles is approximately spherical, and the surface is relatively smooth. At the same time, the researchers used Ts. The pressure curve characterizes the compressibility of the material. It is found that in the range of 2-10 kN, the TS of Andrographis paniculata-HPMc composite particles increases by 67% to 96%. The compressibility within the range of 10 kN, the larger the value, the better the compressibility. As a result, compared with the Andrographis paniculata-HPMc equal proportion physical mixture, the AuTcC corresponding to the Andrographis paniculata composite particles increased by 96.1%, mainly because the HPMc was evenly distributed on the surface of the Andrographis paniculata particles after co-treatment, which showed the same improvement trend as the Andrographis paniculata extract. In addition, the composite particles were mixed with 1% magnesium stearate and 1% micropowder silica gel for automatic continuous direct compression, and randomly selected for characterization of friability and tablet weight differences. Require.

Li et al. studied with dried ginger ethanol extract, kudzu root ethanol extract, poria cocos ethanol extract, ganoderma lucidum water extract, gardenia water extract, tangerine peel pulverization, andrographis paniculata and poria cocos pulverization as model drugs, and also obtained Similar results, the improvement of its fluidity is mainly due to (1) the improvement of particle structure, compared with irregular, rod-shaped or needle-shaped raw materials, most of the composite particles after co-processing are spherical or spherical; (2) after co-processing The particle size increases and the particle size distribution is more uniform; (3) After co-processing, HPMC can effectively coat the raw material particles, increase the distance between the original particles and reduce their contact area and van der Waals force, and summarize the relevant mechanism of its compression formability (1) HPMc has good adhesion and compression properties, and an effective coating layer is formed on the surface of the original particle of traditional Chinese medicine; (2) after co-processing, compared with the raw material and the physical mixture of the same prescription, the cohesiveness of the composite particle significantly increased, and plastic deformation mainly occurred during the entire compression process; (3) after co-treatment, the composite particles showed a more uniform particle size distribution, smaller bulk density and tap density, indicating that the composite particles existed in a looser state, Therefore, there is more volume reduction in the tableting process, thereby improving its compressibility; (4) The fluidization encapsulation process is complex, and several phenomena will appear simultaneously, such as particle-to-particle collisions, solid bridge and/or liquid bridge generation, The interfitting between particles, etc., all help to improve the compressibility of materials.

In summary, the key direct compressibility of composite particles prepared by co-processing, such as fluidity, compressibility, etc., was significantly improved, and the direct parameters of fluidity (such as cI, HR, AR, etc.) were significantly decreased, and the direct parameters of compressibility ( Such as TS, AuTCC, etc.) have increased significantly, while tablet weight difference and friability are used as indirect indicators of fluidity and compressibility respectively, which also meet the relevant requirements of the 2020 edition of "Chinese Pharmacopoeia"; the parameters of the compression process of composite particles have also improved. For example, the compression ratio, yield pressure, tablet force, rapid elastic recovery rate, friction work, etc. have decreased significantly, which further proves that the composite particles have excellent compression properties and are more suitable for the production of tablets. In addition, Li et al. found that when HPMc was used as a modifier, the moisture absorption rate and equilibrium moisture absorption of traditional Chinese medicine composite particles prepared by fluidized bed bottom spray coating technology decreased. In the future, it is necessary to pay attention to whether the composite particles can significantly improve parameters such as agglomeration of traditional Chinese medicine powder.

4. HPMC surface modification method

At present, spray drying technology and fluidized bed bottom spray coating technology are widely used co-processing technologies. Among them, the former is easy to prepare spherical composite particles with relatively small particle size, while the latter is easy to obtain large particle size and relatively rough surface. Composite particles, both of which help to improve the fluidity and compressibility of materials. Dong et al. used HPMC as the coating material to physically modify mannitol and calcium carbonate by the above two co-treatment methods, and found that both of them can significantly improve the compressibility, fluidity and drug loading of raw materials and excipients, but the latter The compressibility, lubrication sensitivity, and drug loading of those produced by spray-drying coating are mostly spherical porous particles with smooth surface, while those produced by fluidized bed bottom spray coating mostly present large-scale porous particles. Non-spherical aggregates with irregular surface enhance the contact area and mechanical interlocking between particles, which is more conducive to direct powder compaction.

5. Outlook

Tablets are playing an increasingly important role in the development of oral solid preparations. The powder direct compression process is the preferred method for its production, which can significantly improve production efficiency and reduce costs, and has more advantages for drugs that are unstable when exposed to heat and humidity . At present, although the powder direct compression process has made some progress in the field of traditional Chinese medicine pharmaceuticals, it is mainly based on excipients, and the traditional Chinese medicine tablets included in the current "Chinese Pharmacopoeia" all use the tableting process after granulation, indicating that HPMc is promoting There is great potential in the development of the direct compression process of traditional Chinese medicine powder, and there is a lot of room for its application in tablet production, but most of the relevant research focuses on the improvement of fluidity and compressibility, and the use of HPMC will be to a certain extent Inhibits the dissolution of active ingredients. In the future, parameters closely related to industrial production such as lubrication sensitivity and hygroscopicity of HPMC-modified composite particles can be further studied; when improving the direct compression performance of powders, the dosage should be reasonably controlled, and other structural modifications (such as forming pores structure), so as to better promote its application in powder direct compression technology.