Zolpidem is effective in reducing the time to sleep onset and increasing total sleep time; however, its effect on sleep maintenance has not been consistently demonstrated. The hypnotic effects of Zolpidem have been reported primarily in the first 3 hours postdose which can lead to subtherapeutic effects on sleep maintenance in the later portion of the night for some patients [ 5 ]. Moreover, melt granulation is one of the most widely applied processing techniques in the array of pharmaceutical manufacturing operations due to its simplicity and easy scaleup [ 6 — 8 ].
In recent years, melt granulation has also been successfully employed to improve the dissolution rate of poorly soluble compounds increasing the bioavailability of these kinds of drugs, [ 9 — 11 ] and in the development of CR formulations [ 12 — 14 ] and masking the bitter taste of an active drug [ 15 , 16 ]. Hence, the purpose of present investigation was to develope controlled-release tablet of Zolpidem tartrate by using polyethylene glycol PEG [ 17 ] as melt binder, Hydroxypropyl methylcellulose HPMC K4M and Polyvinylpyrrolidone PVP K30 as matrixing agent and filler, respectively, which would release the drug for prolonged period of time in view to maximize therapeutic effect of the drug and in an effort to expand the coverage of sleep complaints and overcome the lack of efficacy in sleep maintenance.
Zolpidem tartrate was procured from Tripada Pharmaceuticals Ltd. Fine chemicals, Mumbai, India. All other materials and chemicals used were of either pharmaceutical or analytical grade. Then mass was removed from the hot plate and subjected to scrapping until it attained room temperature. The coherent mass was passed through 22 mesh, and the resulting granules were resifted over 44 meshes to separate granules and fines.
The granules were collected and mixed with talc and magnesium stearate. A 3 2 randomized full factorial design was employed in the present study. In this design, 2 factors were evaluated, each at 3 levels, and experimental trials were performed for all 9 possible combinations. The prepared formulations were evaluated for assay, friability, and hardness and in vitro release study. The results of evaluation parameters are shown in Table 2. Statistical treatment was carried out to the factorial design batches using design expert DX8 software.
The dissolution profile of all batches was fitted to various models such as zero order, first order, Higuchi [ 18 ], Hixon and Crowell [ 19 ], and Korsmeyer et al. From the in vitro dissolution study, it was found that hydrophobic binder MCC wax and bees wax have more sustaining effect on the release of drug than stearic acid and cetyl alcohol it is due to its hydrophobic nature. Hydrophilic binder PEG gave good drug release compared to all the other binders, which is due to its hydrophilic nature.
HPMC K4M hydrophilic was selected as a matrixing agent considering its widespread applicability and excellent gelling activity in controlled-release formulations. PVP was also selected in formulation because it helps in releasing loading dose from the formulation in the 1st hour which is required for the therapeutic effect of formulation. The dissolution profile for 9 batches showed a variation i. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries i.
Table 4 shows the results of analysis of variance ANOVA , which was performed to identify insignificant factors. Data were analyzed using Design of Expert version 8. The coefficients for full and reduced models for response variables are shown in Table 4. The results of statistical analysis are shown in Table 4. The results of model testing are shown in Table 4.
The kinetics of the dissolution data were well fitted to zero order, Higuchi model, and Krossmayer-Peppas model as evident from regression coefficients in Table 5. In case of the controlled-release formulations, diffusion, swelling, and erosion are the three most important rate controlling mechanisms. Formulation containing swelling polymers show swelling as well as diffusion mechanism because the kinetic of swelling includes relaxation of polymer chains and imbibitions of water, causing the polymer to swell and changing it from a glassy to rubbery state.
The resulting blend was subjected to compression using compression machine KMP—8, Kambert mini rotary compression machine employing 6-mm round standard concave punch. The total weight of tablets was kept constant at 70 mg. In addition to being used for biphasic release system preparations, they were used as single units to evaluate the effect of compression on the structure and in vitro dissolution behavior.
The powder used to coat the core was formulated to obtain a quick release of the drug. Sodium starch glycolate was used as a superdisintegrant for the immediate release of the drug. Avicel PH was used due to its good compaction and disintegration properties. LubriTose AN contains anhydrous lactose and glyceryl monostearate which act as tablet diluent and lubricant, respectively.
The active ingredient and excipients were accurately weighed and passed through mesh 40 and then blended for 10 min before compression. For the preparation of the biphasic delivery system, the die of the tableting machine was first filled manually with the half the amount of the fast-release component, and then, core tablet was placed carefully at the center. The remaining half of the fast-releasing powder was added to coat the core tablet. The formulations differed in the grade and concentration of HPMC used in the preparation of the core tablet and in the concentration of sodium starch glycolate used in the immediate-release part.
Even the amount of zolpidem tartrate used in core and coat part was varied as per requirement. Compressed core tablet systems were prepared by direct compression, using 9-mm standard concave punch. The total weight of tablet obtained was mg. The dissolution media used were mL of 0. At predetermined time intervals, mL sample was withdrawn and was replaced with an equal volume of fresh dissolution medium. The cumulative fraction of the drug release was calculated from the total amount of zolpidem tartrate and plotted as a function of time.
The US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have suggested that two dissolution profiles can be considered similar if f 2 is between 50 and 19 , The suitability of several equations that are reported in the literature to identify the mechanisms for the release of zolpidem tartrate was tested with respect to the release data. The data were evaluated according to the following equations:.
The value of n indicates whether the release mechanism is Fickian diffusion, case II transport, or anomalous transport. Values of n greater than 0. Drug-excipient compatibility study was conducted by preparing homogenous mixture of excipients with drug and filled in transparent glass vials. Samples were observed periodically for any physical change at 1, 2, and 3 months, and Fourier transform infrared spectroscopy FTIR and differential scanning calorimetry DSC studies for the samples were conducted after 3 months.
Differential scanning calorimetry studies of pure drug and polymers as well as drug—polymer mixtures were performed using a Toledo DSC Mettler Star SW 9. Tablets were strip packed and stored at stability chamber Tabai Espec Corp. After 3 months, tablet strips were taken out from the chamber and tested for appearance, hardness, thickness, assay, and in vitro drug release.
The physical properties weight, thickness, hardness, and friability of the core tablets and biphasic delivery system tablets for all the formulations were noted. The thickness of the core tablets was in the range of 2. The prepared core tablets as well as biphasic delivery system tablets in all the trials possessed good mechanical strength with sufficient hardness of 5. The percentage of drug content among different formulations of the tablets ranged In the release of the drug from the core tablets, different dissolution profiles were observed.
From the plots of Fig. It was found that the cumulative percentage of drug release decreases with increasing the polymer concentration as well as with the increase in viscosity grade of the polymer. Thus, F14 was considered as optimized formula. The values for the release rate constants K 0 , K 1 , K H , K K , and K s , the correlation coefficients R 2 , and the release exponent n are considered. The correlation coefficient R 2 was used as an indication of the best fit, for each of the models considered.
For the optimized formulation F14, Korsmeyer-Peppas plot showed linearity with correlation coefficient R 2 0. The results for the cores R 2 slightly higher for the Higuchi model, 0. The interaction between the drug and the excipients often leads to identifiable changes in the infrared IR spectra of the drug excipient mixture in the formulation. The IR spectra of drug excipient mixture were compared with the standard spectrum of zolpidem tartrate. The IR spectrum of pure drug showed a peak at 2, A tertiary amine stretching gave a doublet at 1, The spectrum reveals the characteristic peaks for the important functional groups in the drug structure are retained, indicating no significant interaction between the drug and the excipients used in the formulations.
The overlay of IR spectra is shown in Fig. Differential scanning calorimetry enables the quantitative detection of all processes in which energy is utilized or produced endothermic or exothermic phase transformations. The DSC thermogram of pure drug, pure polymers, and blends of drug and polymers overlay is shown in Fig. The physical properties weight, thickness, hardness, and friability of the core tablets and compressed core tablet systems for all the formulations were within the acceptable limits.
For all formulations, upon contact with the dissolution media, the modified-release tablets rapidly disintegrated into the fast-releasing phase and the matrix core tablets. The prompt tablet disintegration was due to the presence of sodium starch glycolate, which swells very quickly on contact with the dissolution medium. After the initial phase, the release was dependent on the composition of the matrix core, in particular, the grade and concentration of HPMC.
The ability of the HPMC particles to hydrate and form a gel layer around a core is well-known and is essential to sustaining and controlling the release of a drug from the matrix Throughout the dissolution test, a continuous gel layer formed in the HPMC matrix core was responsible for guiding the release of the drug. In the biphasic delivery system developed by Maggi et al. F14 was considered as optimized formula by calculating the similarity factor.
For the optimized formulation F14, Korsmeyer-Peppas plot indicated that Fickian diffusion is an important mechanism. The results for the cores indicate super case II transport. However, the analysis of the results applying these mathematical models is purely empirical, and no definitive conclusion can be drawn concerning the dominant mass transport mechanisms. Compatibility studies reveal that the drug is compatible with the all excipients used in the formulation.
The stability studies concluded that the formulation can withstand to the general stress conditions of temperature and humidity. The results obtained with the dissolution tests showed that the release profile is dependent on both the grade and amount of polymer in the core tablet. The developed formulations were matched with Stilnoct ER for drug release profile.
The similarity factor f 2 and dissimilarity factor f 1 were calculated, and it was concluded that the formulation F14 of this modified-release biphasic delivery system tablets would be a promising formulation for the treatment of chronic insomnia by supporting sleep maintenance. This formulation followed the USP limits for drug release of zolpidem tartrate extended-release tablets. The biphasic release systems of selective drugs rationally can meet the benefits of pharmacotherapy.
Anglo-French Drugs and Industries Ltd. Bangalore, India for providing necessary facilities to carry out this research work. National Center for Biotechnology Information , U. Published online Nov Anjan Kumar Mahapatra , N. Sameeraja , and P. Anjan Kumar Mahapatra, Phone: Received Mar 28; Accepted Oct 9. Abstract Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. Preparation of Biphasic Delivery System Tablets The biphasic delivery system tablets were prepared by compressing the core components to a smaller tablet, forming a central core, followed with a compression of coat component powder mixture to produce a final tablet.
Slow-Release Component Core Tablet The modified-release tablets were prepared by direct compression method. Fast-Release Component External Layer The powder used to coat the core was formulated to obtain a quick release of the drug. Biphasic Delivery System For the preparation of the biphasic delivery system, the die of the tableting machine was first filled manually with the half the amount of the fast-release component, and then, core tablet was placed carefully at the center.
Release Drug Data Modeling The suitability of several equations that are reported in the literature to identify the mechanisms for the release of zolpidem tartrate was tested with respect to the release data. The data were evaluated according to the following equations: First-order model 24 , Higuchi model 26 , Korsmeyer-Peppas model 28 , Compatibility Studies Drug-excipient compatibility study was conducted by preparing homogenous mixture of excipients with drug and filled in transparent glass vials.
Dissolution profiles from compressed core tablets, fast component, and core tablets of formulation F Fourier Transform Infrared Spectroscopy The interaction between the drug and the excipients often leads to identifiable changes in the infrared IR spectra of the drug excipient mixture in the formulation. Differential Scanning Calorimetry Differential scanning calorimetry enables the quantitative detection of all processes in which energy is utilized or produced endothermic or exothermic phase transformations.
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