An investigation into the optimization of release profile of lithium carbonate from matrix-type tablets containing carbopols, pemulen and eudragits

Iranian Journal of Pharmaceutical Research (2003) 33-38 Received: June 2002 Accepted: February 2003 An Investigation into the Optimization of Release Profile of Lithium
Carbonate from Matrix-type Tablets Containing Carbopols, Pemulen and
Eudragits
Reza Aboofazeli*, Seyed Alireza Mortazavi Department of Pharmaceutics, School of Pharmacy, Shaheed Beheshti University of Medical Sciences and Health Services, Tehran, Iran. Abstract
The influence of various polymers on the release rate of lithium carbonate from matrix-type tablets was investigated in an attempt to formulate a sustained release solid dosage form. For this purpose, tablets containing 450 mg of lithium carbonate along with various amounts of Carbopol 934P, 971P, 974P, Pemulen and Eudragit RLPO as retarding agents and inactive ingredients (e.g. PVP, Avicel or starch) were prepared using wet granulation technique. Tablets prepared were initially placed in a phosphate buffer solution for 7 h and those formulations from which a minimum of 80% lithium carbonate released, were selected for coating process. The amount of drug released was determined by using atomic absorption spectroscopy. The dissolution rate of enteric coated matrix-type tablets were then evaluated in both acidic and basic mediums (1 h and 11 h, respectively). The results showed that Pemulen and Carbopol 971P are not suitable polymers for preparing tablets with desirable release profile, at all concentrations examined. However, it was observed that Carbopol 934P, 974P and Eudragit RLPO are capable of producing tablets with desirable release pattern, at concentrations of 2, 1.5 and 3%, respectively. Tablets containing Eudragit RLPO were found to have the greatest drug release profile, while Carbopol 974P showed the slowest release rate.
Keywords: Lithium carbonate; Carbopols; Eudragits; Matrix-type tablets; Drug release
profile; Sustained release; Formulation. Introduction
their sensitivity to lithium as well as their Archive of SID
Many of the side effects of lithium are dose used for the control of bipolar disorders (manic related. Initial adverse effects of lithium therapy depression). It is also used in recurrent or include nausea, diarrhea, vertigo, polyuria with unipolar depression as an alternative to polydipsia and muscle weakness. Those effects tricyclics. Lithium has a narrow occurring at therapeutic serum concentrations therapeutic/toxic ratio. Recommended include anorexia, constipation or diarrhea, therapeutic serum concentrations range from epigastric discomfort, headache and vertigo (1). 0.4 to 1.2 or even 1.4 mmol/l, with higher Lithium is readily and completely absorbed concentrations required for acute mania. from the gastrointestinal tract when taken as However, it is necessary to emphasize that one of its salts and peak serum concentrations serum concentrations should be adjusted for are obtained between 0.5 to 3 hours after each patient, since individual patients vary in ingestion from conventional solid dosage forms, depending upon formulation of the preparation (2, 3). Following the administration * Corresponding author: E-mail: [email protected] of lithium salts, there is a wide inter-subject R Aboofazeli, SA Mortazavi / IJPR 2003, 2: 33-38 variation between both the serum Company (Iran). Magnesium stearate, polyvinyl concentrations obtained following a given dose, and between those required for therapeutic obtained as gifts by Tolidarou Pharmaceutical effect. On the other hand, there is only a narrow Company (Iran). Diethyl phthalate (DEP) and margin between therapeutic and toxic plasma cellulose acetate phthalate (CAP) were gifted concentration of lithium. Therefore, individual titration of lithium dosage is essential to ensure constant appropriate concentrations for the Construction of calibration curves matrices containing a suitable polymer can Calibration curve of lithium carbonate in a provide a sustained release formulation, capable pH 6.8 phosphate buffer was constructed by of controlling the release rate of the drug over preparing standard solutions containing 0.5, 1.0, an extended period of time and producing a 1.5, 2.0, 2.5 and 3.0 mg/l lithium carbonate. desirable blood serum level with little or no fluctuation, which in turn lead to a decrease in determined at 671 nm, using atomic absorption the occurrence of drug toxicity. In this spectroscopy. The calibration curve was found investigation, attempts were made to formulate to be linear over the concentration range of a sustained release dosage form of lithium 0.5 – 3.0 mg/l, and hence was used to determine carbonate with an optimum release pattern, the amount of lithium carbonate released from using various Carbopols, Pemulen and Eudragit RPLO as retarding polymers. In the first step, Calibration curve of the drug in an acidic various formulations were prepared and medium (0.1 N HCl) was also constructed by characterized from the physico-chemical point preparing standard solutions containing 0.5, 1.0 of view. In the second step, the appropriate formulations were selected for coating stage determination of absorbance, using atomic and finally the dissolution behavior and release absorption spectroscopy. A linear relationship kinetics of coated tablets were evaluated. was obtained over the concentration range Experimental
Preparation of matrix-type tablets Materials
Matrix-type tablets containing 450 mg of Lithium carbonate powder, monobasic lithium carbonate along with various amounts potassium phosphate, dibasic sodium of Carbopols, Eudragit RLPO and inactive phosphate, hydrochloric acid, ethyl alcohol and ingredients (such as PVP, Avicel and microfine acetone were all purchased from Merck cellulose) were prepared by the wet granulation Chemical Company (Germany). Various technique. In the first step, active and inactive Carbopols, in Archive of SID
ingredients (except magnesium stearate) were Carbopol 971P (C971P), Carbopol 974P weighed and screened through a 60-mesh sieve. (C974P) and Pemulen were obtained from B.F. Required materials were then combined and the Goodrich Company (UK). Eudragit RLPO and mixtures wetted by ethyl alcohol and then Avicel pH 101 were gifted by Akbarieh granulated using a laboratory granulator Table 1. Composition (%) of lithium carbonate matrix-type sustained release tablet formulations, prepared by wet granulation technique.
Formulation
C934P Avicel
PVP C974P Avicel PVP Starch C971P Avicel PVP Pemulen Avicel PVP Eudragit Avicel PVP
* In formulation A7, water was used as granulating solvent. ** Gelatin was used instead of PVP. Optimization of release profile of lithium carbonate from ,,, laboratory coating pan, positioned at a specific obtained were then screened through a 14-mesh angle. The coating solution was sprayed on the sieve and dried at room temperature for 24 h. tablets, while the heated air was directed into Finally, dried granules were passed through a the pan and onto the tablet bed surface. following the addition of a given amount of magnesium stearate, they were compressed into The amount of lithium carbonate released determined using a USP apparatus I (rotating basket) dissolution tester, set at 100 rpm and a temperature of 37 ±0.5°C (4). Dissolution according to the monograph of lithium test was performed in both acidic and basic carbonate extended release tablets in United media. In this study, tablets were placed initially in 900 mL of a pH 1.5 hydrochloric acid solution for about 1 h and 5 ml samples were taken after 0.5 and 1 h, while the volume In order to prepare the coating solution, of the dissolution medium was kept constant by solvent (acetone–ethyl alcohol mixture) and replacing it with equal volumes of fresh polymer (CAP) were mixed in a beaker and solution. After 1 h, the dissolution medium was stirred until a clear solution was obtained. completely removed and replaced with 900 ml Plasticizer (DEP) was then added to the of pH 6.8 phosphate buffer solution and solution, while stirring. Tablets were placed in a samples (5 ml) were removed in predetermined Table 2. Results of quality control tests carried out on lithium carbonate matrix-type sustained release tablets
containing Carbopols, Eudragit RLPO or Pemulen, prepared by wet granulation technique . Formulation Hardness
Friability
Weight variation (%)
Max. drug released after 7 h
(Kp) (n=10)
(%) (n=10)
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R Aboofazeli, SA Mortazavi / IJPR 2003, 2: 33-38 intervals over 11 h. The amount of drug inactive ingredients, prepared in this study. released in both acidic and basic media was Table 2 indicates the results of physico- calculated, using the corresponding calibration chemical quality control tests (including friability, hardness, weight variation, assay and dissolution time) performed on the formulations Results and Discussion
In the past few decades, sustained release released at different time intervals, attempts drug delivery systems have attracted a great were made to establish an appropriate limit, deal of attention in pharmaceutical researches, mainly due to their therapeutic advantages. information and some adverse effects of lithium Because of the importance of lithium carbonate carbonate and also the physiology of the in the treatment of manic depression, the gastrointestinal tract. Diarrhea is one of the preparation of a sustained release dosage form common adverse effects of lithium carbonate could not only increase the efficacy of (5). Studies have shown that an ideal sustained treatment and patient compliance, but also can release preparation should release its drug produce desirable blood concentrations and content mainly in the small intestine. decrease the incidence of adverse effects. Conventional tablets and capsules enter the In this study, various Carbopols, Eudragit small intestine after 3-6 h, in the presence of food (6). On the other hand, following the polymers in an attempt to formulate a sustained release matrix-type dosage form of lithium formulations, peak concentrations are delayed carbonate. Based on the results of and may occur between 3 to 6 h after preformulation studies, it was observed that administration (7-10). Considering the fact that tablets with desirable physical characteristics absorption of lithium is rapid and complete could be prepared by using the wet granulation throughout the small intestine, one could technique, due to the improvement of conclude that a high percentage of drug should flowability and compressibility of lithium be released from tablets after 7 h in dissolution carbonate granules. Table 1 shows the test. Therefore, not only the peak plasma composition of various formulations containing concentrations and optimum bioavailability lithium carbonate and different polymers and could be achieved, but also the occurrence of ase
ele 60
Formulation A6
Formulation A7
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Formulation A8
Formulation B8
Formulation E5
Figure 1. Release pattern of lithium carbonate from various coated, sustained-release matrix-type tablets in acidic and
basic media (n=3).
Optimization of release profile of lithium carbonate from ,,, Table 3. Dissolution time limits established for matrix-
when placed in phosphate buffer medium, these type sustained release lithium carbonate tablets. formulations were selected for the enteric- Drug released (%)
In the final stage of this study, the amount of lithium carbonate released from enteric coated tablets was calculated over 12 h in both acidic and basic media (1 h and 11 h, respectively). diarrhea would be prevented. Table 3 shows Figure 1 depicts the release profiles obtained the release percent range of lithium carbonate from the enteric coated tablets. The kinetic of for a sustained release preparation, considered drug release from the coated formulations was also assessed. The kinetic models evaluated When investigating the influence of C934P were zero order, first order and Higuchi model. on the release rate of lithium carbonate from It should be noted that due to the presence of an tablet matrices, polymer concentrations ranging acid-resistant film, the amount of the drug from 1.5 – 5% were employed. Tablets released after 1 h in acidic medium was containing greater than 2% C934P were found to release their drug content relatively slow and formulations. The release kinetic of drug in produced an undesirable drug release profile, buffer solution was evaluated and analyzed while a polymer concentration less than 3% was statistically. The results obtained by assessing found to be suitable for producing a desirable the drug release patterns showed that over a release in the screening dissolution test, falling period of 11 h (in buffer medium), all enteric coated formulations most likely follow a Higuchi model of release. Table 4 indicates the the release rate of lithium carbonate, polymer correlation coefficients of drug release curves, concentrations higher than 1.5% were observed calculated over 11 h, based on the above- to produce undesirable release profiles. Results have also shown that Eudragit RLPO contents between 3-5% caused relatively slow and aqueous medium, form a hydrogel due to water unacceptable drug release profiles. However, by absorption. As the thickness of this hydrogel reducing the amount of polymer present within layer increases (depending upon the amount of the formulation from 5 to 3%, along with an water absorbed), the release rate decreases (11). increase in Avicel content and a decrease in The formation of a hydrogel layer seems to be PVP concentration, the drug release pattern potentially higher for Pemulen and C971P improved, in terms of the determined limits. compared to C934P and C974P, and therefore, even a reduction in the amount of polymer, did retarding agents, in all polymer concentrations not improve the drug release profile in Pemulen examined, an undesirable and unacceptable and C971P-containing formulations. The
drug release ra Archive of SID
addition of starch to formulation resulted in a the polymers investigated, C934P, C974P and further decrease in release rate, despite its Eudragit RLPO were found to be suitable for disintegrating property. This effect could be preparing matrix-type lithium carbonate tablets. explained by considering the fact that swelling As can be seen in Table 2, all preparations of starch would possibly further increase the possessed desirable characteristics. However, thickness of the hydrogel layer produced by since more than 80% of the drug released from Carbopols and hence, influence drug release formulations A6, A7, A8, B8 and E5 after 7 h, from the matrices. It seems that Eudragit RLPO can not form a hydrogel layer around matrices, Table 4. Correlation coefficients of drug release curves
for enteric coated tablets, based on three kinetic models.
and therefore, its content was kept constant at Dissolution
Correlation
der to prevent disintegration of tablets Formulation Time
(h) Zero First
in the dissolution medium. A decrease in the content of PVP as well as an increase in the amount of Avicel, caused a high penetration of dissolution medium into the matrices and hence R Aboofazeli, SA Mortazavi / IJPR 2003, 2: 33-38 In conclusion, C934P, C974P and Eudragit RLPO were found to be suitable polymers for preparing sustained release tablet matrices containing lithium carbonate. References
(1) Reynolds JEF (ed). Martindale, The Extra Pharmacopoeia, Royal Pharmaceutical Society, London, (1996) 318 (2) Hollister LE. Antipsychotic agents and lithium. In: Katzung BG. ed. Basic and Clinical Pharmacology. Appleton and Lange, Norwalk – Connecticut, (1990) 432 – 448 (3) Shargel L and Yu ABC. Pharmacokinetic and pharmacodynamic parameters for selected drugs. In: Applied Biopharmaceutics and Pharmacokinetics. 3rd edition, Prentice – Hall, New York, (1993) 594 (4) The United States Pharmacopeia XXIII and National Formulary XVIII. U.S. Pharmacopeial Convention, Easton (1995) 1790-1840, 1981, 2180-2192 (5) Ehrlich BE and Diamond JM. Lithium Absorption: Implications for Sustained Release Lithium Preparations. Lancet. (1983) 306 (6) Shargel L and Yu ABC. Modified release drug products and targeted drug delivery systems. In: Applied Biopharmaceutics and Pharmacokinetics. 3rd edition, Prentice – Hall, New York (1993) 225-265l (7) Llabres M and Farina JB. Design and evaluation of sustained release tablets of lithium in fat matrix and its bioavailability in humans. J. Pharm. Sci. (1991) 80: 1012 – 1026 (8) Crammer JL, Rosser RM and Crane G. Blood levels and management of lithium treatment. Brit. Med. J. (1974) 3: 650-654 (9) Arancibia A, Corvalan F, Mella F and Concha L. Absorption and disposition of lithium carbonate following administration of conventional and controlled release formulations. Int. J. Clinic. Pharmacol. Therap. Toxicol. (1986) 25: 240-245 (10) Marini JL and Sheard MH. Sustained release lithium carbonate in a double blind study. Serum lithium levels, side effects and placebo response. J. Clinic. Pharmacol. (1976) 276-282 Archive of SID
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