Keizo Tomita

Polyvinyl alcohol (PVA) is a copolymer of vinyl alcohol and vinyl acetic acid. Many modified PVAs with various functional groups and numerous properties have been developed, and their basic characteristics determined by polymerization and saponification.

 synthesized PVA copolymer by the copolymerization of acrylic acid (AA) and methyl methacrylate (MMA) with PVA and developed hard capsules that could be filled with liquids, such as Macrogol 400.

As PVA copolymer film has extremely low oxygen permeability, its use as a film coating was evaluated. It was found that PVA copolymer could be used to coat tablets and/or granules if it was processed into a low-molecular-weight solution that could be sprayed.

This article primarily focuses on the properties of PVA copolymer, and its use as a film coating for tablets and microparticles. It also includes the results of scale-up experiments.

The PVA copolymer developed for encapsulation copolymerizes PVA, AA and MMA at high degrees of polymerization to provide capsules with the desired hardness and solubility.

When a solution of the polymer is sprayed by the two-fluid method, which is usually used for film coating, the liquid drops are not micronized and become thread-shaped dust (Figure 1) that cannot be sprayed. This thread-forming property is the result of the formation of an extensive elastic network in the polymer solution. To contend with this problem, the development of a low-viscosity polymer suitable for spraying was attempted by decreasing PVA's degree of polymerization.

PVA with a degree of polymerization of 500 and an 88% degree of saponification was copolymerized with AA and MMA at the same copolymerization ratio used for encapsulation. The PVA copolymer solution obtained was sprayed and the droplet size was measured with a laser diffraction droplet size analyser (LDSA1400A; Tohnichi Computer Applications Co. Ltd, Japan).

As shown in Table 1, the mean particle size and size distribution of the liquid drops approximated those of hypromellose solution (HPMC [TC-5; Shin-Etsu Chemical Co. Ltd, Japan]) for film coating, which was used as a control, indicating that this copolymer makes spray coating possible. 

Table I Droplet size at spraying of water solution. 

PVA copolymer can be dissolved in water at room temperature, but dissolves more easily with heating and yields a slightly emulsified turbid solution.

The solution has low viscosity, even at high concentration, and adjustments for high-concentration solutions are possible as viscosity can be lowered by heating. The practical elongation of the film obtained from the polymer is approximately 34 times greater than that of HPMC.

 The addition of plasticizer is not required, which eliminates the the risk of drug–plasticizer interaction, as well as any appearance change that could be caused by plasticizer migration.

The film obtained is clear and transparent, and can be used for white tablets as there is no discolouration caused by the remaining functional groups, as is seen in a cellulose polymer system. It also has the advantage of further increasing the filling rate pigment volume concentration as it has a high-adhesive strength with other film coating materials, such as pigments, opacifiers and lubricants. The results of this evaluation are described hereafter. 

Strength of film adhesion to tablet core.

 A total of 5 mg of PVA copolymer or HPMC was coated on 150 mg tablet cores containing 10% wax for sustained release with embossing.

Figure 2 shows cross-section scanning electron microscope (SEM) of the film-coated tablets. The PVA copolymer film tightly adhered to the embossing, but the HPMC film lifted loose, resulting in a loss of definition. 

The film on the tablet surface was cut along the circumference of the tablet edge and was attached to a load cell (AutographAG500B; Shimadzu Corporation, Japan) with adhesive tape and then pulled at a rate of 20 mm/min to determine the force required to tear the film from the tablet surface. The force required to detach the film was 1.103 N for the PVA copolyme, four times higher than for the HPMC-based film at 0.321 N. 

The use of a PVA copolymer-based film can solve the problems associated with lack of film adhesion (e.g., film peeling or logo bridging) to tablets containing large amounts of waxy excipient or a lubricant. 

 A total of 11.5 mg of PVA copolymer was coated on 270 mg tablet cores that contained 100 mg of ethenzamide and 15 mg of anhydrous caffeine. Drug dissolution was determined using the Method 2 dissolution test from the Japanese Pharmacopoeia.

Figure 3 shows the ethenzamide dissolution rate in four different test fluids, with the HPMC-coated sample used as a control. These results confirmed that the properties of PVA copolymer were pH-independent and that it dissolved as rapidly as the HPMC-coated sample. In addition, the PVA copolymer-coated tablet did not taste bitter when administered orally as the taste of anhydrous caffeine was sufficiently masked. 

The surfactant added to the test solution as a solubilizing agent in the dissolution test did not influence drug release from the PVA copolymer-coated tablets. 

 A cast film on a glass plate, prepared using the same ingredients as the tablet coating film, was used in the physical strength test as a substitute for the tablet coating film.

The 100-tablet samples used for the dissolution test in the previous section were loosely filled into a high-density polyethylene container and packed in a paper box. This was then subjected to a 6-face drop test from a height of 1 m and a rotary drum drop test in accordance with JIS Z0200.

 The samples were not cracked, chipped or deformed, confirming that PVA copolymer-coated tablets have an extremely high resistance to impact. 

 The PVA copolymer has a hydroxyl group on a side chain and there was concern that drying time of the copolymer would be reduced at scale-up. To test this possibility, 303000 tablet cores with a weight of 264 mg/tablet were loaded into a general production-scale model Doria Coater DRC 1200 (POWREX, Japan) to conduct coating under the conditions shown in Table 2. The machine coated 9.5 mg/tablet during the 5 h required for spraying and provided tablets of good appearance. However, when a room-temperature solution was sprayed onto the tablets, they tended to be cohesive. To correct this, the coating solution was heated to 50 °C, which eliminated cohesiveness and provided an excellent adhesion rate of ≥95%. Unlike HPMC, PVA copolymer does not gel with heating. 

 The permeabilities of the PVA copolymer, HPMC and gelatin are shown in Table 3. The oxygen permeability of the PVA copolymer is 10 to minus 11th mol/(m

 ×s×PA) that of HPMC, and 10 to minus 9th mol/(m

 ×s×PA) that of gelatin. The copolymer's outstanding performance as a gas barrier means that it could have a wide range of applications, including the protection of easily oxidized drugs, the masking of a drug's offensive odour and preservation of aromas of fragrant materials. 

These properties lead to the following considerations: 

Inhibited oxidation — currently, the means to protect drugs that are easily oxidized includes tablet forms (e.g., band-sealed capsules and coated tablets) and sealed packaging containing a deoxidizer. However, these means have limited efficacy and require many processing steps. In contrast, the PVA copolymer's strong oxygen-blocking ability is expected to protect against oxidation with a simple film coating. Tablet cores with a mixture of ascorbic acid and a trace of copper sulphate as a pro-oxidant were coated with 10% PVA copolymer and 10% HPMC. The tablet cores were stored in air (ambient oxygen) and in a nitrogen-filled desiccator as a stability test. The results are shown in Figure 4. Both tablet core and HPMC-coated tablet core showed significantly decreased vitamin C content. Conversely, the PVA copolymer-coated tablet core showed only a slight decrease, which was almost the same as the decrease in the case tablet core stored in nitrogen. This confirmed the copolymer's protection ability as a barrier against oxygen.

Masking of offensive odour and preserving aromas of fragrant materials — it is common for drugs to produce offensive odours and for the aroma of fragrant materials to dissipate with time. It was thought that PVA copolymer could prevent these undesirable developments. Granules containing 10% acetylsalicylic acid were coated with 5, 10 and 15% PVA copolymers. The acetic acid odour that developed with time was quantified with a model SF-105 odour sensor (Toshiba System, Japan). Additionally, a sensory test was conducted using 20 panelists. The uncoated sample generated a strong acetic acid odour with an intensity of 390 Hz. In contrast, samples coated with ≥10% PVA copolymer showed an odour intensity of 280 Hz, which could be masked so that the panelists experienced very little odour.

Protection against whisker crystallization — if caffeine-containing drug products are stored for a long time, cloudiness and whiskers will be generated on the surface of the products and on the packaging, which can reduce API content and change the proportions of the product mixture. These events result from multiple factors and often cannot be prevented by normal film coatings.

 A series of 255 mg tablet cores containing 50 mg caffeine and 30 mg guaiacol potassium sulfonate were coated with 13 mg PVA copolymer. These tablet cores were heated and stored at 60 °C in a sealed vial for 1 month to examine the copolymer's ability to prevent whisker formation. At the end of the test, the inner surface of the vial containing tablet cores was clouded with whisker, but there was no cloudiness on the inner side of the vials containing coated tablets, indicating that PVA copolymer should prevent whisker formation with a normal coating quantity. This showed that PVA copolymer could prevent whisker formation with a normal coating volume. 

As mentioned previously, the viscosity of PVA copolymer is significantly lower than that of HPMC solution. This suggested the possibility of a high-concentration coating and the coating of microparticles. When acetaminophen (ACA) and isopropylantipyrine (IPAP) were mixed, comelting occurred and the meting point decreased (Figure 5). The possibility of microparticle-coating is tried to be demonstrated to inhibit the comelting by coating microparticle ACA and then mixing the coated-ACA with uncoated IPAP. Using a Wurster fluidized bed granulator model FD-MP-01 (POWREX) as a coating machine, 15% of ACA was coated with PVA copolymer with a liquid concentration of 15%. Figure 5 shows the result of a thermal analysis test on the mixture of unprocessed or coated ACA and IPAP. As indicated in the figure, both the mixed product of coated ACA and IPAP reduced melting point immediately after the test as well as with time, and ACA microparticles were coated with the copolymer. Thus, the interaction between these drugs was avoided (comelting did not occur in Figure 5). 

Factors responsible for difficult coating of microparticles include the easily induced phenomenon of poor fluidization because of static electricity induced by the coating. However, particles coated with PVA copolymer were slightly charged, which meant that good fluidization could always be ensured. Thus, the grain size distribution of unprocessed and coated ACA varied very little. 

The Japanese Pharmaceutical Excipients Directory includes the use of partially saponified PVA as a binder.

  PVA copolymer can be used as a binder based on the characteristics mentioned earlier, but herein the use of a coated tablet as a binder is presented. 

HPMC is mixed with sucrose solution, which causes salting-out and reduction of its binding force. In contrast, the PVA copolymer was compatible with the sucrose solution and provided excellent bonding properties, while showing no delay or slowing of dissolution and no reactivity with some drugs. In addition, the coating process did not require special techniques and provided coated tablets with a good appearance. 

The initial aim was to develop hard capsules using the PVA copolymer that could be filled with liquids. However, because of PVA copolymer's extremely low-oxygen permeability, its use as a film coating was also investigated. It was found that this polymer has many outstanding characteristics as a coating film, such as unexpectedly strong adhesion to tablet cores, flexibility without any plasticizer and good physical strength, as well as other advantages not reported in this article, such as suitability for printing with a high gloss. A safety test for this polymer was completed under the guidelines in 

Drug Approval and Licensing Procedures in Japan

, and we are now preparing to obtain a use precedent for this polymer.

The excellent characteristics of the polymer are confidently expected to contribute to the future development of medicinal drugs.

We express our thanks to Daido Chemical Corporation and Nisshin Kasei Co., Ltd for providing the PVA copolymers for this research. 

works for the CMC Development Laboratories of Makoto Noami in Japan. 

works for the Technology Development Unit for Industrial Technology Laboratories in Japan. 

Articles

The use of PVA copolymer-based film can solve the problems associated with lack of film adhesion... to tablets containing large amounts of waxy excipient or a lubricant.