The purpose of this study was to determine what combination of carriers would result in a core tablet that would be suitable for use in aqueous enteric film coating process. A relatively simple formulation of microcrystalline cellulose (MCC) and partly pregelatinized starch (PGS-P) was found to impart the required properties. MCC in the formulation provided the necessary compaction to produce a tablet to withstand the mechanical process of filming. P-GPS solution provides the features and is responsible for the characteristics of stability in this sensitive to moisture, the application enteric coated. We also found that the P-PGA could be used to reduce the harmful effects of superdisintegrants in the preparations.
In recent years, acetylsalicylic acid (ASA, also known as aspirin) was prescribed a variety of indications. Besides its use as an analgesic, antipyretic and anti-inflammatory, ASA is not indicated for use in the prevention and treatment of heart disease and stroke. Other studies are currently underway investigating the possibility of ASA to strengthen the immune system, treatment of cognitive impairment and reduced risk of colon cancer and ovarian cancer. A low daily dose of 75-81 mg, ASA is commonly used in preventive treatment. Historically, the SAA is considered a potential gastric irritation (1) and studies have shown that the incidence of intestinal gastric side effects may increase with regular use (2) The enteric-coated tablets is therefore desirable to prevent stomach irritation or those taking daily treatment with ASA.
Aspirin is a medicine sensitive to moisture and can be hydrolyzed into acetic acid and salicylic acid when exposed to moisture and high temperatures (3). As the coating process will be presented to the ASA tablets at high temperatures and humidity, it is important that the formulation is resistant to moisture interaction. Mitrevej Hollenbeck and found that a field is generated around the hydrophilic ASA crystals under conditions of high humidity and the combination of ASA with some disintegrating hydrophilic condensation in the vicinity of the glass can be produced ASA (4). The disintegration were studied sodium starch glycolate (SSG), croscarmellose sodium (CCS), crospovidone and colloidal silica. In the process of film coating, aqueous Faroongsarng and Peck found that the depth of water penetration into the tablet core can be directly related to the concentration and type of decomposition used in the formula (5). Further work of Bashar Al-Taani study aqueous solutions of ASA tablets coated confirmed that the penetration of moisture during the coating process was not only the formulation of charge, but may be directly related to the stability of final ASA coated tablet (6).
A review of the ingredients in five products purchased commercially ASA concluded that, in most cases, a major excipients were microcrystalline cellulose (MCC) and some form of starch. The use of additional excipients, including disintegrants (such as CCS and SSG), lubricants and sliding wide. The five products were packaged in sealed paper, high density polyethylene (HDPE), three of which contain carbon / silica desiccant packets. The aim of this study was to determine what combination of excipients found in commercial products SAA would result in a tablet core that is suitable for use in aqueous process enteric coating film. Ideally, enteric coated tablets should have excellent storage stability, accelerated without the fuse packing extra precautions (and expensive) programs as a desiccant for other special packing materials.
Materials and Equipment
Aspirin
1040 (acetylsalicylic acid crystals USP 40-mesh, Rhodia, Cranbury, New Jersey, USA) was used as the active material. The excipients used in the study were part of pregelatinized starch (PGS-P) (Starch 1500, Colorcon, West Point, Pennsylvania, USA), MCC (Emcocel 50M, Penwest, Patterson, New York, USA ), SSG (Explotab, Penwest) CCS (Ac-Di-Sol, FMC, Princeton, New Jersey, USA) and stearic acid NF (purified powder of quality plants OLEOTEC Ltd., London, UK). Packaging materials used were 85 mL bottles of high density polyethylene with aluminum seal (drugs, plastic and glass Co., Boyertown, Pennsylvania, USA) and desiccant packets (3964, Sud-Chemie Performance Packaging Bethlehem, New Mexico, USA). The coating materials used were an aqueous enteric coating (Opadry II), both manufactured by
Colorcon.
Dried ingredients in a blender for 16 rooms with double walls (Patterson-Kelley Co., East Stroudsberg, Pennsylvania, USA). The tablets were compressed on an instrumented press Piccola 10 station rotary (Riva, Buenos Aires, Argentina). Tablet Strength was measured with an analyzer Multichek (Erweka, Milford, Connecticut, USA). Furthermore vented coating pan 15 “(coat II, O’Hara Technologies, Toronto, Canada) was used for coating. A dissolution test station (VK 7010, a device that VanKel, Cary, North Carolina, USA . UU.) was used for testing drug release. An HPLC (high-resolution chromatography high performance liquid system (Alliance 2690, Waters Corp., Milford, Massachusetts, USA) was used to determine the free salicylic acid concentration.
Methods
mixture and Tablet Preparation
six formulations (see Table I), composed of constant levels of ASA and the oil and different levels of MCC, PGS-P, CCS and SSG each mixture is dried for 15 minutes in the mixer double wall . The lot size of each mixture was 5kg. Each of the six mixtures were compressed to the rotary tablet press with 10 stations to 7.0 mm standard concave tool. The target tablet weight was 162.0 mg and the compaction force was adjusted to produce tablets with a tensile strength of 6.0 to 7.0 kp. The coating of tablets was performed on one side of the pan 15-inch ventilated, equipped with a gun. The charge was 3 kg of bread. A sub-layer Opadry II dispersed in water (15% w / w) was applied to obtain a theoretical gain of 2% by weight of the six tablets of tablets of batches. lower layer application was immediately followed by an enteric coating composition Sureteric dispersed in water (15% w / w) and used to obtain a theoretical weight gain of 10%. A coat of Opadry II dispersed in water (15% w / w) was applied to the tablets obtain a weight gain of 2%. The six tests were conducted using the same process temperature coating recommended application rates and operating conditions. In general, the use of a lower layer beneath the enteric coating is optional and depends largely on the quality of the tablet core. As the six lots that contained several ingredients, a sub-layer has been applied to the six lots so that the enteric coating is not affected by minor changes in the surface of the tablet. Wearing a coat is also optional, but many commercial products have a finish coat applied to the base color.
Dissolution and free salicylic acid test
solution and no evidence of salicylic acid were performed according to the USP 23 monograph for ASA tablets. The tablets were analyzed according to the USP 23 monograph for delayed-release tablets ASA.
Tablet hardness testing
uncoated tablets were tested for diametral tensile strength before and after storage under accelerated conditions. The average result was reported 20 tablets tested.
packaging and stability
Samples
uncoated tablets of each formulation is packaged in bottles of high density polyethylene (120 tablets per bottle). The tablets of each formulation was filled in the same way: a series of samples has been packaged without desiccant, a second set of samples was filled with a desiccant pack in every bottle. All bottles were induction (paper) closed and under accelerated conditions, 40 degrees Celcius/75% humidity (RH) for 3 months.
Results and discussion
uncoated tablets
SAA
dissolution test conducted in acetate buffer (pH 4.5) revealed that only a single batch containing MCC as an excipient not reach 80% drug release within 20 minutes. The results of the dissolution after storage under accelerated conditions showed little change from the first tests.
More significant are the results of mechanical content of the tablets after exposure to accelerated temperature and humidity conditions. The only pills ASA and MCC has lost 8.57% of the hardness of the tablets while the tablets containing the combination of MCC-PGS-P showed the lowest decrease in the hardness of the tablets, with a loss of 3, 0%. The use of any SAC or SSG in combination with CMC results in a loss of more than 36.3% of the tablet strength. Interestingly, when the same levels of SCC or SSG has been used in the tablets of the combination of P-PGA and MCC, the loss of hardness of the tablets was less deep. Comparing the levels of salicylic acid free uncoated tablets, the initial time and after 3 months at 40 degrees Celcius/75% relative humidity, the results showed a similar trend to the hardness of the tablet.
USP limit for free salicylic acid in aspirin tablets coated with no more than 0.3%. After 3 months in accelerated conditions, the tablets containing only MCC or MCC excipient which is discussed or SSG SAC significantly increased levels of salicylic acid free and meets the requirements of USP. The combination of CMC-P-PGS showed virtually no degradation of SAA over time in adverse conditions, and increased free salicylic acid was negligible.
showed that the P-SGP used in this study has a lower propensity to absorb moisture than any of the SAC or SSG and consume less moisture in a compressed under high humidity (7). This may partly explain the positive effects observed with the use of this formulation. The data also suggest that the P-PGA may be able to catch or retain moisture in the formulation, thereby delaying the interaction with moisture
ASA.
Initial results
coated ASA tablets
After coating, the tablets of all formulations have a good appearance. None of the tablets showed no signs of defects during testing or after coating. The tablets of all batches passed the testing phase with no release of acid dissolution of ASA after 2 hours in HCl 0.1 N during the test phase buffer (pH = 6.80, as with the results of the tablets uncoated solution, containing only the MCC and ASA do not meet the specifications of the USP not less than 80% ASA released in 90 minutes. In fact, the other five formulations of up to 80% of ASA release within 20 minutes .
coated tablets stability of the results
After 3 months of storage at 40 ° Celcius/75% relative humidity, some tablets containing SSG exposed CSC or softening of the coating film and adhesion of the tablets each in bottles of high density polyethylene. This occurred in samples which were packed with and without desiccant packs. All the tablets show signs of defects at this time were considered failures of stability.
The results
free salicylic acid-coated tablets are very similar to the results obtained for the tablets. The USP limit for free salicylic acid in tablets coated ASA, 3.0%, is higher than the uncoated tablet specification. After 3 months in accelerated conditions, the tablets containing only MCC as an excipient described above, but acceptable, levels of salicylic acid free. The combination of MCC with SCC or SSG resulted in a substantial increase over 5.0% salicylic acid without the whole, therefore did not meet the requirements of USP. Again, the most acceptable results were observed for tablets containing MCC and PGS-P as excipients, which showed no increase of free salicylic acid was used to dry an increase of only 0, 91% when packaged without desiccant . The addition of P-PGS significantly reduces the amount of degradation of ASA in tablets containing MCC combines with the SSG, or CCS, which had unacceptable levels of salicylic acid free.
It was interesting to note that the addition of desiccant packs
bottle has not been sufficient to eliminate or significantly reduce the harmful effects of superdisintegrants. Of the six formulations, tablets containing MCC excipient alone or the combination of MCC-PGS-P meets the desired stability performance requirements of good looks, resistance to acids and acceptable levels of salicylic acid free. The formulation with only MCC does not meet the requirements of the delayed release dissolution of ASA in buffer either initially or after 3 months of storage at accelerated conditions. The combination tablets containing CMC-P-PGS has excellent slow-release dissolution initially and after 3 months of relative humidities Celcius/75 40%.
Conclusions
The results of this study provides a relatively simple formulation using a combination of ASA and PGS MCC as an excipient P-primary. MCC in the formulation provides the necessary compaction to produce a tablet to withstand the mechanical process of filming. Starch solution provides the features needed in this sensitive to moisture, the application enteric coated. The formulation without the use of additional superdisintegrants would be very suitable for the process of aqueous film coating and final coated tablets do not require the use of specialized packing materials. We also found that the P-PGA could be used to reduce the harmful effects of superdisintegrants in formulations. It would also reduce the costs of raw materials. The next phase of this study will focus on optimizing the necessary levels of enteric coating and the extension of the enteric coating process.
Thanks
The authors thank Rhodia Inc. for the gift of the AEA used in this project. In addition, we thank David for his support Ferrizzi analytical Colorcon.
May 2001 article in Pharmaceutical Technology Europe. Reproduced Publication No.: 0462. To view accompanying tables and figures, please visit http://www.colorcon.com/literature/marketing/ex/Starch 1500/enteric_articlenc.pdf.
References
BK Martin, “the formulation of aspirin,” in HS Bean, AH Beckett and JE Carless, Eds, Advances in Pharmaceutical Sciences, vol. 3 (Academic Press, London, UK, 1971), p. 148.
Batterman RC, “Comparison of buffered and unbuffered acetylsalicylic acid,” New Engl. J. Med 258, 213 to 219 (1958).
Merck Index, twelfth edition, 886, Merck Research Laboratories (1996).
A. Mitreveg and RG Hollenbeck, “Influence of hydrophilic excipients interaction of aspirin and water,” Int. J. Pharm. 14, two hundred forty-three to two hundred and fifty (1983).
D. and G. Faroongsarng Peck, “inflammation of the tablets in water-based coatings I: a simple model that describes the measurement of swelling and water penetration for insoluble tablets containing a super disintegrant,” Drug developer. Ind. Pharm. 17 (18) 2439-2455 (1991).
B. Al Taani “physical interactions of the water by superdisintegrants pharmaceutical tablet cores containing water for the paintings,” Ph.D. Thesis, Department of Industrial and Physical Pharmacy at Purdue University, West Lafayette, Indiana, USA (May 1999).
Cunningham, C., “corn starch and superdisintegrants in direct compression formulation, Pharm. Manufacturing. Rev. 22-24 (December 1999).
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