hard gelatin capsules pdf

2022.07.31
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hard gelatin capsules pdf

A.; 22. Connors, K. A.; Amidon, G. L.; Stella, V. J.; ANVISA - Agncia Nacional de Vigilncia Sanitria; 13. 0000535406 00000 n 0000535062 00000 n

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Raj, T. J. S.; Bharati, C. H.; Ranga, K.; Raoa, K. R.; 11.

These are important factors that must be taken into account so that the use of HPMC capsules be a viable alternative to gelatin in manipulation pharmacy and in the pharmaceutical industry for developing formulations containing ampicillin.

0000549371 00000 n The average values of ED% are shown in Table 3 and the graphical representation is shown in Figure 2. The ampicillin used for the formulations development was weighed and the test was performed either to a specific number of taps or until the volume measured in the graduated glass cylinder changes by less than 2%, using tapped density or apparent volume tester (Pharma Test PT-TD1, Germany). A portion of 50 g of ampicillin for the development of the formulations was put in the sieve and submitted to sieving for 20 min. Gianotto, E. A. S.; Machado, H. T.; Miglioranza, B.; Fregonezi-Nery, M. M.; 3. The angle of repose determination was performed using the methodology proposed by Gil14 employing automated powder tester (Pharma Test PTG-2, Germany). The dissolution medium consisted of 900 mL of distilled and degassed water, and was kept at 37 C with speed of 100 rpm. 0000413352 00000 n 0000452612 00000 n This fact can be explained because HPMC is a forming polymer of hydrophilic matrix used to promote a slower release of the drug conditioned in the capsules.20-23 The value found for the reference medicine (90.47%) resemble the values obtained for the capsules elaborated with HPMC, although this product is made from hard gelatin capsule. The determination of the weight of the capsules containing 500 mg of ampicillin was performed according to the Brazilian Pharmacopoeia.15 To perform this test, we used 20 capsules of each manipulated formulation (A and B) and the reference product. Aliquots were transferred to the test tube with lid, heated in water bath at 75 C for 30 min and cooled rapidly. For the statistical analysis of data obtained with the dissolution profiles, a comparative method was used between them and the efficiency of dissolution (ED%). Statistical analysis of the dissolution profiles. 0000016730 00000 n 0000619171 00000 n The capsules should meet the demands of weight variation, disintegration time, assay and tenor uniformity of actives described in the monograph.12,13 Therefore, the aim of this study was to develop capsules starting from hard gelatin and HPMC involucres, to evaluate the quality of the final products and to compare them with each other and with the medicine reference. 0000534799 00000 n 0000615178 00000 n The ED% was calculated from the percentage curves of drug dissolved versus time. 0000004983 00000 n

0000006128 00000 n The dissolution efficiency of the five samples (reference, GEL-A, GEL-B, HPMC-A and HPMC-B) showed significant differences among groups (P> 0.05) in ANOVA. 636 76 0000550107 00000 n hbb2g`b``3 1x4> * 0000002661 00000 n In the first case, the three involucres are made of hard gelatin and in the second case they are made of HPMC.

Azevedo, R. C.; Ribeiro, G. P.; Arajo, M. B.; 5. Furthermore, the compaction force used in the industry for the development of the reference may be delaying the drug release in dissolution medium. 0000020032 00000 n The formulations with HPMC capsules showed lower percentages of drug dissolved (99.67%, HPMC-A and 87.70%, HPMC-B) than the gelatin (100.18%, GEL-A and 101.16% GEL-B). Thus, the problems involving hygroscopic drugs, sensitive to the humidity and with problems in their interaction with the gelatin molecules can be circumvented.6,7, The capsules produced with HPMC involucre guarantee the hygroscopic drugs stability, such as ampicillin, a bactericidal antibiotic of wide spectrum that acts against aerobic gram-negative bacteria.8,9 In the case of ampicillin, it is possible to foresee some possible degradation reactions because the ring beta-lactam is susceptible to hydrolysis (Figure 1).10,11. 0000614785 00000 n Monteiro, L. M.; Souza, A. E.; Gianotto, E. A. S.; Nery, M. M. F.; Duarte, J. C.; Freitas, O.; Casagrande, R.; Baracat, M. M.; * The determination of the granulometric strip was done mechanically using an agitator of sieves (Bertel, Brazil). 0000007466 00000 n This trial was conducted in triplicate following the specific method described in the Brazilian Pharmacopoeia.16 Standard solution was used at a concentration of 1.25 mg mL-1. Bonfilio, R.; Mendona, T. F.; Pereira, G. R.; Arajo, M. B.; Tarley, C. R. T.; 18. This fact can be explained once the hydrophilic matrix, when in contact with the dissolution medium, swell and form a gelled layer that controls the subsequent entrance of water into the matrix and drug release, prolonging its release.21-23 The speed of water penetration in the matrix system determines the mode of drug release. Because of the delay of the drug release in initial times of the dissolution profiles, it becomes necessary to evaluate the drugs that can be conditioned in the HPMC capsules. The procedure performed in this technique is described in Test and dissolution profiles. The disintegration time of capsules with HPMC involucres (7 min, HPMC-A and 6 min, HPMC-B) was higher than the capsules elaborated with gelatin involucres (5 min for both formulations); this fact can be explained due to the nature of the involucre.

0000465702 00000 n The titration was performed with volumetric solution of 0.01 M sodium thiosulfate, and starch was used as indicator solution. 0000019290 00000 n 711 0 obj <>stream

These capsules were purchased from market (Genix and Capsugel, Brazil), presenting humidity values of 13.8% (GEL) and 5.8% (HPMC), according to the certificate of analysis. 0000005418 00000 n The formulations have been differentiated according to their content, in formulation A (ampicillin trihydrate, magnesium stearate, colloidal silicon dioxide and croscarmellose sodium) and formulation B (only ampicillin trihydrate), being denominated GEL-A, GEL-B, HPMC-A and HPMC-B. e-mail: Four formulations were developed containing 500 mg of ampicillin in hard gelatin capsules (GEL) and HPMC capsules. The water determination test showed lower humidity tenors for HPMC capsules than gelatin capsules. This fact associated with features of ampicillin, such as increased size, density, and hygroscopic end up making the manipulation difficult because of the resistance of the flow of powders in manual encapsulator and difficulty of accommodation in the same involucres. For the dissolution profiles were used five time points: 10, 15, 20, 30, 45 and 60 min, with subsequent replacement of the dissolution medium. ampicillin; gelatin; hydroxypropyl methylcellulose, Evaluation of hard gelatin capsules and hydroxypropyl methylcellulose containing ampicillin, Graziella Gonalves Weigert; Anile Posser Ineu; Patrcia Gomes* 0000615352 00000 n 0000012679 00000 n 0000001853 00000 n 0000505773 00000 n

Two formulations (A and B) were developed. After testing, aliquots of 10 mL were removed from the dissolution medium, filtered and diluted in cuprum sulfate buffer to appropriate concentration (22 g mL-1). Furthermore, by having hygroscopic characteristics, ampicillin requires greater protection against humidity and the HPMC is a capsule with low humidity tenor when compared to the gelatin, which ensures the stability of drugs with this characteristic. When the gelatin capsule is ingested, it allows the penetration of water, causing its hydration and drug release in a few min. Recebido em 23/1/11; aceito em 1/7/11; publicado na web em 9/8/11. Hard gelatin and HPMC involucres have different compositions therefore it is necessary to study the development of formulations involving these involucres as well as the evaluation of the final product quality. The fact is relevant because the ampicillin is susceptible to hydrolysis.10,11, The analytical curves developed for the test and dissolution profiles presented a determination coefficient (R2) of 0.9969 and 0.9988, respectively. In the case of drugs which need a quick release, the use of HPMC capsules must be evaluated with caution so that less damage in the therapeutic action of the medicine be observed. c`wT t :QvZ * @D:v2x7p01TamP,`dg`y1J O A'30hX60` % W The choice of hydrophilic polymer in the matrix formulation can provide an appropriate combination of the swelling mechanisms, dissolution or erosion and determine the release kinetics in vitro.21 According to previous work,22 the drug incorporation in hydrophilic matrix systems is the most used method to prolong drug release dosage forms for oral use.

The results of mean weight, assay, disintegration time, and water determination test for the hard gelatin capsules (A and B), HPMC capsules (A and B) and reference medicine is evidenced in Table 1. The values of relative standard deviation (RSD) of mean weight were 1.79% (reference medicine), 2.60% (GEL-A), 2.10% (GEL-B), 2.61% (HPMC-A) and 2.19% (HPMC-B). Ku, M. S.; Li, W.; Dulin, W.; Donahue, F.; Cade, D.; Benameur, H.; Hutchison, K.; 8. This comparison cannot be performed with the reference medicine and HPMC capsules, because they are of different constitution. In high concentrations, the linear chains of HPMC form a tangle and result in a gelatinous layer, fairly consistent, hindering the release of the active principle. 0000615305 00000 n Fortunato, K. A.; Doile, M. M; Shumcker, I. C.; Shucko, S. K.; Silva, M. A. S.; Rodrigues, P. O.; 23.

The assay of the examined formulations (A and B) and the reference medicine was performed through iodometric method. The high density found for the ampicillin (0.5557 g cm-3) provided the choice of capsule number 00 (0.95 mL). 0000011836 00000 n

The determination of water content was conducted by Karl-Fischer method using the capsules content (Reference, GEL-A, GEL-B, HPMC-A and HPMC-B).15 A Karl-Fischer autotitratiom unit (Mettler, Brazil) was set up according to the manufacturer's instructions. The choice of the appropriate size of the capsule for the drug to be produced is performed according to the density parameters of the powder to be encapsulated and the volume of possible capsules to be used. The values obtained in this test demonstrate that the excipients added to the formulation A and the ones in the reference medicine did not aid in the disintegration process, when compared to the formulation containing only the ampicillin (formulation B). 636 0 obj <> endobj Ampicillin anhydrous reference standard (98.35%) was obtained from Brazilian Pharmacopoeia (Brazil). This fact can be explained because in both comparative cases (GEL versus reference medicine and HPMC-A and HPM-B) the involucres have the same nature.

e-mail: The ED% was calculated by the ratio between the area under the curve (AUC) and total area of the graph was expressed in percentage.17 The graphs were obtained by Graph PadPrism software and ED% values were compared by one-way ANOVA and accomplished by Tukey post-test. 0000545598 00000 n 0000007240 00000 n 0000517285 00000 n The analytical curve was prepared from a standard solution of ampicillin RS concentration of 100 g mL-1. We opted for the addition of some excipients in the formulation A, since the amount of the present drug in the formulation is not always enough to make up the chosen capsule as well as due to other characteristics of the drug.

0000017827 00000 n 0000517355 00000 n In the case of the ampicillin, whose plasmatic pick is reached in 2 h, a concern is not observed regarding the use of the HPMC capsule for this drug. Then, the data were treated statistically by one-way analysis of variance (ANOVA) using Graph PadPrism software (version 4.0, California, USA). (English), https://doi.org/10.1590/S0100-40422012000200010. 0000619569 00000 n 0000009821 00000 n They are considered one of the best ways to condition drug substances because they protect them from the light, air and humidity action.

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The quality control consists in an indispensable stage of the process for medicine manufacture, regardless of its production scale. 0000003552 00000 n 0000535379 00000 n The granulometry above 600 m found for the ampicillin trihydrate involved a complex manipulation of the drug in magisterial scale, making the accommodation of the powders in the manual encapsulator. 0000624184 00000 n

0000011152 00000 n 0000008089 00000 n Other tested formulations showed significant differences (P <0.05, P <0.01 and P <0.001), which can be explained mainly by the difference in the nature of the involucres that directly influence the dissolution efficiency.

The assay values presented that ranged from 90.06 to 114.62% for HPMC-B and GEL-B, respectively. Kamel, S.; Ali, N.; Jahangir, K.; Shah, S. M.; El-Gendy, A. To calculate the amount of ampicillin indeed dissolved in the medium, it was compared to that obtained with the ampicillin reference standard (RS) at concentration of 0.0022% (w/v) prepared under the same conditions. The samples were diluted to concentrations similar to the pattern. 0000003694 00000 n The amount of dissolved ampicillin was determined by using a spectrophotometer UV/VIS (Shimadzu UV1650PC, Japan) and detection at a wavelength of 320 nm. 0000517468 00000 n 0 xref The granulometry found in the test for the ampicillin was superior to 600 m. endstream endobj 710 0 obj <>/Filter/FlateDecode/Index[66 570]/Length 42/Size 636/Type/XRef/W[1 1 1]>>stream %%EOF None presented linearity deviation. This may be related to the present excipients in the reference medicine (lactose, methylcellulose, stearic acid and magnesium stearate), which are different from the excipients used in the B formulation. It was observed that with increasing amounts of HPMC in the formulations it is possible to get a reduced release of the drug, which can be evidenced in the dissolution tests.23 With the use of HPMC in capsules, this polymer characteristic may promote a release different from the one observed with the capsules produced with gelatin, delaying the release of the drug and consequently modifying its kinetics of release. Regarding the dissolution test (Table 2) the hard capsules produced with gelatin showed higher percentage values of dissolution (100.18 and 101.16% for GEL-A and GEL-B, respectively) when compared to the capsules produced with HPMC (99.67 and 87.70% for HPMC-A and HPMC-B, respectively). Six units of each formulation were subjected to dissolution test and twelve to the dissolution profile. Although the formulations have different constituents, the excipient present in the formulation A and the reference medicine do not seem to interfere in the dissolution efficiency of the capsules in analysis. 0000008000 00000 n HPMC is a cellulosic derived that is moisturized quickly, but swells and takes longer to disintegrate in body temperature; it is also more soluble in lower temperatures, such as 10 C.18,19 The gelatin is a soluble protein in hot water and in the gastric liquid, where it quickly releases its contents soluble in biological fluids at a room temperature.3 Capsules of the reference medicine showed higher values for the test compared the disintegration of gelatin capsules, probably due to compression existing in the process of industrial scale production. These results obtained are in agreement with the pharmacopoeia specifications15,16 and they show a proper process of manipulation. 0000012048 00000 n 0000545197 00000 n hb```e`X`o "l@Q6 U98=apte4Vs0^L%F}^ [&kL%:T%A JDEWSxGc^UW],;;==X{A+ $(1&%%%c @b`IA(G PPA-7 82iaK,^14` As gelatin has a high humidity degree (13 to 16%), hard capsules have been manufactured using a material of vegetable origin, the hydroxypropyl methylcellulose (HPMC) with the main objective of producing involucres with smaller humidity tenor (3 to 8%).6 The introduction of HPMC based capsules have appeared as an alternative to the conventional use of the hard gelatin capsules.

Ogura, T.; Matsuura, S.; Futuya, Y.; 6. 0000008456 00000 n At very low concentrations, these cellulose gels have very low viscosity, allowing almost immediate release of drugs.21. Capsules are solid pharmaceutical forms usually destined to the oral use that present a good acceptance for part of the population.1-3, The involucres used for the development of capsules are usually constituted by gelatin, water, coloring and other materials including preservatives and processing aids. 2. 0000016617 00000 n L%1O"xX'0=c`C!C F l*^*016~`cli`x`*p Z2]AQ W S Fahs, A.; Brogly, M.; Bistac, S.; Schmitt, M.; 21. Stability studies are necessary to evaluate the real contribution of the hard gelatin and HPMC capsules relation to the protection of drugs conditioned in these capsules. 0000002468 00000 n , Centro Universitrio Franciscano, Brazil, Text 0000015420 00000 n

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0000007354 00000 n Korolkovas, A.; Frana, F. F. A. C.; 10. patriciagomes0@yahoo.com.br, Curso de Farmcia, Centro Universitrio Franciscano, Rua dos Andradas, 1614, 97010-032 Santa Maria - RS, Brasil. (EN), Stay informed of issues for this journal through your RSS reader, Text The reference medicine showed values of mean weight similar to the capsules with the formulation A (612.90 mg), which denotes the quality of the product elaborated in magisterial scale. The medicine reference Amplacilina (Eurofarma, Brazil) was also employed in this study. Because of the delay of the ampicillin release observed in the dissolution profiles, it becomes necessary to evaluate the drugs that can be conditioned in the HPMC capsules. It is soluble in hot water and in the gastric liquid, which quickly liberates its content.3, However, main Pharmacopoeias, such as the European, Japanese and American also allow the use of other appropriate materials besides gelatin. , <<41A0BCFC819D394ABE199AE6BCDDB4F6>]/Prev 1243352/XRefStm 2468>> 0000413267 00000 n Furthermore, the f2 factor indicated the similarities between the dissolution profiles of the reference medicine and GEL-A (99.95%) and GEL-B (99.86%). This test was performed for the powder mixture formulation for the development of hard gelatin and HPMC capsules. 0000456290 00000 n The collection time for the dissolution test consisted of 45 min. 0000622280 00000 n 0000004250 00000 n After the method application, calculations were performed to determine the granulometric strip of the ampicillin.5. The gelatin used in capsules is justifiable because it is a nontoxic substance, widely used in food, and it is readily soluble in biological fluids at room temperature.4,5 Also, for being a protein, the gelatin is digested and absorbed. The disintegration test was carried out following the established methodology for Brazilian Pharmacopoeia15 using the disintegration tester (Pharma Test PTZ-E, Germany). 0000004650 00000 n The final product quality was evaluated by testing for quality control and the results were in agreement with the Brazilian Pharmacopoeia. 0000013371 00000 n

This instrument is suitable for testing powder Flow Time, the measurement of the cone angle (angle of repose) of the collected powder mound, measuring the weight, calculating the density and the volume of the powder cone as well as the EP/USP "Flowability" results which is to measure the flow time of 100 g of sample through a specified pouring nozzle. The excipients contained in the pharmaceutical dosage form were all of pharmaceutical grades and acquired from different distributors. 0000006043 00000 n 0000003420 00000 n %PDF-1.4 % In the manipulated capsules, it could be observed that the formulation containing only the drug (formulation B) presented lower values of mean weight (579.6 and 584.88 mg for GEL-B and HPMC-B, respectively), while the capsules containing excipients (formulation A) showed higher values (624.6 mg, GEL-A and 619.72 mg, HPMC-A). 0000021782 00000 n 0000549712 00000 n 0000535812 00000 n

However, there are no literature values for this drug granulometry. endstream endobj 637 0 obj <>/Metadata 64 0 R/PageLabels 61 0 R/Pages 63 0 R/StructTreeRoot 66 0 R/Type/Catalog/ViewerPreferences<>>> endobj 638 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>>/Rotate 0/StructParents 2/TrimBox[0.0 0.0 581.102 822.047]/Type/Page>> endobj 639 0 obj <> endobj 640 0 obj <> endobj 641 0 obj <> endobj 642 0 obj <> endobj 643 0 obj <> endobj 644 0 obj <> endobj 645 0 obj <>stream 0000014498 00000 n trailer This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Quality control for pharmaceutical dosage form. The linear range comprised 2-27 g mL-1 for the dissolution profiles and 16-28 g mL-1 for the dissolution test. 0000453137 00000 n

startxref H\@FyZv/$UV \ctc1.|9bp:)jnZlL?W8C}}>6jx:]wOpNs^f^y_G_iw{5u)bax[}/Om=>ox[8G:Uy6~f?$rl_2-&zZAP TLgByy@9. The Tukey test indicated the differences among the capsules in study. This equipment has round sieves for particle size analysis with 8.5 or 3 inches in diameter. 0000006739 00000 n There was no significant difference (P> 0.05) in the ED% from the capsules GEL-B (66.78%), GEL-A (60.97%) and the reference medicine (62.37%) as well as between HPMC-A (74.92%) and HPMC-B (76.18%). f `

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Keywords: ampicillin; gelatin; hydroxypropyl methylcellulose. By using a forming polymer of colloidal matrix in encapsulated excipient, the dissolution of the capsule is affected promoting a controlled release.20, Several studies suggest the use of HPMC in formulations in order to promote modified releases of drugs. 0000006776 00000 n patriciagomes0@yahoo.com.br, , Santa Maria, 0000512245 00000 n 0000000016 00000 n The granulometric analysis of the ampicillin for the development of the capsules is an important parameter to be established; it represents a direct influence on the manipulation of the capsules in magisterial scale. The titration was performed until the disappearance of the blue color. The time limit established for this test for hard gelatin, HPMC and the reference drug capsules was 45 min.15. 0000020955 00000 n 0000009212 00000 n After the completion of the angle of repose, we observed that the mixing of powders and the ampicillin alone have an angle greater than 40, which characterizes a very weak flow.5 This characteristic observed for the mixture of powders destined to the production of the capsules shows that even after the addition of a small amount of excipients to the formulation A, no improvement in the flow of powders was observed. Dissolution studies were performed according to the monograph of the pharmaceutical dosage form contained in the Brazilian Pharmacopoeia.16 Basket apparatus was used in the dissolution equipment (Pharma Test PTWS-3E, Germany). 0000413197 00000 n The standard operational parameters call for a drop rate of 250 strokes per min with a drop height 3.0 mm. 0000452329 00000 n 0000618063 00000 n This study aims to develop and evaluate formulations containing ampicillin in capsules of gelatin and hydroxypropyl methylcellulose (HPMC). 0000009848 00000 n 0000018887 00000 n The results of this study suggest that differences exist between the hard gelatin and HPMC involucres used in the development of capsules containing ampicillin 500 mg, mainly in relation to disintegration, and dissolution tests.