INTRODUCTION:

The vulnerability of controlled release formulations when co-ingested with alcohol represents a current major concern of regulatory agencies¹. Concomitant administration of medications and alcohol especially ethanol can significantly disturb the drug concentration in blood plasma. This is mainly due to the failure of dosage form in the presence of alcohol.

Failure of the dosage form may be due to the sensitivity of some excipients against alcohol². It may also be due to the higher or lower solubility of drug in alcohol compared to water. Failure of dosage form means initial burst release or dose dumping which leads to toxicity to the patient.

As per the report of World Health Organization (WHO), more than 3 million people died due to the harmful effect of alcohol means 1 in 20 deaths. In these deaths, more than three-quarter are only men amongst all which suggest men are more abused to alcohol compared to women. Overall, the harmful use of alcohol causes more than 5% of the global disease burden. In the current scenario, the number of alcohol consumers as well as the consumption of alcohol is increased in the Western Pacific and South-East Asia regions. These regions include China and India which have high population³.

The Food and Drug Administration (FDA) of United States withdrawn Palladone, an extended-release narcotic analgesic capsule of Hydromorphone hydrochloride, from the US market. It is mainly due to fatal adverse reactions" occurred in patient due to the higher concentration of drug in the plasma⁴,⁵. Immediately FDA issued an alert on “risks of ethanol induced dose dumping from oral sustained/controlled release dosage forms”.

Excipients especially polymers make up the huge proportion in the oral solid controlled drug delivery formulation. Polymers are important for controlling the release rate of drug from the dosage form therefore it is important to evaluate their flexibility under the harsh condition of gastrointestinal tract⁶. Additionally, modified release dosage form contains high amount of drug in the formulation compared to other simple formulation since the drug content is intended to be released at a preprogramed rate over a long period of time. It is therefore important to be able to identify polymers or excipients that are alcohol-resistant in order to be able to include them in alcohol resistant pharmaceutical formulations. The oral administration of a dose dumping susceptible formulation with alcohol affects the release regulating barriers of the formulation which could result in an overdose, escalation of pharmacological or side effects, and in the worst case scenario death depending on the drug administered. This is apart from the physiological effect of alcohol consumption which may prolong the gastric emptying rate and onset of drug absorption depending on the calorific content of the alcoholic beverage².

Misssaghi et al. found that HPMC should not cause dose dumping in the presence of alcoholic beverages, even though the textural and rheological properties of the hydrated HPMC may be influenced in the presence of ethanol up to 40% v/v⁷. Levina et al. found that when the HPMC K4 M and K100 M tablets were examined under the hydro-ethanolic media for only 1h, there was no significant change was observed in the drug release but when exposed to hydro-alcoholic media for 12 h, there was significant change in drug release but it was due to change in solubility of drug in media and not due to failure of matrices⁸.

Emeje et al found that hydro-alcoholic media affect the kinetics and mechanism of in vitro dissolution of drug from sustained release tablet of containing carbopol as polymer. Dose dumping is observed mainly due to the interaction between polymer and alcohol⁹.

Larsson et al studied the effect of hydro-alcoholic media on water permeability of film containing ethyl cellulose and hydroxy propyl cellulose (HPC). They found that low HPC containing film shown high water permeability as the concentration of alcohol increases because diffusion through ethyl cellulose increased due to the swelling. Vice a versa, as the concentration of HPC increases, permeability decreases due to blocking of pores by swelling of ethyl cellulose¹⁰.

In this study, the main focus was to assess the influence of hydro-alcoholic media on the multiparticulate formulation containing waxy and hydrophobic polymers. Multiparticulate dosage forms are gaining much favour over single unit dosage forms because of their potential benefits like predictable gastric emptying, no risk of dose dumping, flexible release patterns, and increased bioavailability with less inter and intra-subject variability^11,12. Pellets as a drug delivery system offer not only therapeutic advantages, such as less irritation of the gastrointestinal tract and a lowered risk of side effects due to dose dumping but also technological advantages, for example, better flow properties, less friable dosage form, narrow particle size distribution, ease of coating and uniform packing^11,13.

Lipidic and polymeric materials are widely used to modulate the release of drugs from the pharmaceutical dosage forms to achieve greater safety and efficacy¹⁴. Compritol^® 888ATO (COM), a lipid excipient with IIG and GRAS status along with excellent tableting properties provides sustained and controlled release of drugs wherein release mechanism is based on diffusion and erosion. Drug delivery can be successfully extended for a linger of time mainly due to the lipophilic nature and poor wettability of COM. It can control the drug release of both high and low solubility drugs. It has no effect of pH and also insoluble in ethanol¹⁵. Ethyl cellulose (EC) is a non-toxic, stable, compressible, inert, hydrophobic polymer that has been widely used to prepare pharmaceutical dosage forms¹⁶.

So, the objective of the present research was to assess the vulnerability of controlled release pellets congaing waxy polymer and potent drug in the presence of hydro-alcoholic media.

MATERIAL AND METHODS:

Materials:

Galantamine HBr (GH) was obtained as a gift sample from Zydus Research Centre, Ahmedabad, India. Microcrystalline cellulose (Avicel PH 101) was received from FMC Biopolymer (Philadelphia, PA, USA). COM was obtained from Gattefossé India Pvt. Ltd., Mumbai, India. EC was kindly provided by Dow Chemical International Pvt. Ltd., Mumbai, India. Etahnol (99%) was procured from Ambika Enterprise, Vadodara, India. In-house ultrapure water was used in all experiments. All other chemicals used were of analytical reagent grade.

Preparation of Drug-loaded Pellet:

Pellets were prepared by a laboratory scale extrusion/ spheronization process. The wet mass was prepared by addition of binder solution in a dry powder mixture of GH and Avicel PH 101, mixed for 5 min in blender mixer. The binder solution was prepared by dissolving COM and EC in a blend of isopropyl alcohol and dichloromethane (1:1). The wet mass was immediately transferred to the single screw extruder using 1 mm diameter die plate (Chronimach India Pvt. Ltd., Ahmedabad, India) at a constant screw speed of 30 rpm¹⁷. The extrudates were treated with pregealtinized starch to strengthen extrudes and to get maximum yield of required size pellets. This is the innovative step incorporated between the classical extrusion and pelletization process. The extrudates were further spheronized in a spheronizer (Chronimach India Pvt. Ltd., Ahmedabad, India) using crosshatch plate of diameter 45 cm at 1500rpm for 10 min. at room temperature. The wet pellets were further dried at 40°C for 1h in the hot air oven. Finally, the pellets were passed through a 16–22 mesh and then stored in sealed glass containers.

Optimization of formulation and selection of optimized batch for hydro-alcoholic media effect on drug release:

The optimization of modified release pellets of GH was performed by Central Composite Design (CCD). From the risk assessment analysis, concentration of COM and concentration of EC were selected as the independent variable, studied at three levels each. The central point (0) was studied in quintuplicate. All other formulations and processing variables were kept invariant throughout the study. Percentage drug release at 2h (Y₁), percentage drug release at 6h (Y₂) and percentage drug release at 10h (Y₃) were used separately as the responses in the CCD¹⁸.

Design space is identified using overlaid plot which gives acceptable region combining all contour plots of each response. The overlaid plot was drawn in design expert software. An ideal product is one which satisfies the requirements of drug released at 2, 6 and 12 h. The yellow coloured region shown in the overlaid plot is optimized region. The scientist is free to choose any point within the design space. It is worthwhile to note that FDA requires that the design space be clearly defined in ANDA. Optimization was achieved by computing overall desirability. The software suggested that when the concentration of COM and EC was 0.84 and -0.70 (Coded values), satisfies the three requirements. Rana et al. discussed all the optimization of formulation and validation of model¹⁹. From that article, the optimized batch was selected; composition of the optimized batch was shown in Table 1.

Table 1: Composition of optimized batch

Name of ingredients	Amount (for 1 capsule)	Amount (for 100 capsules)
Galantamine HBr	16 mg	1.6g
COM	16.8 %	3.36g
EC	7.0 %	1.4g
Pregelatinized Starch	2 %	0.4g
IPA: DCM	1:1	1:1
Avicel PH 101	q.s.to 100 %	13.24g

Batch size = 20g

Each capsule contained 200 mg pellet eq.to 16 mg GH

Solubility of Galantamine HBr:

The solubility of the GH in the different hydro-ethanolic dissolution media and pure ethanol was determined spectrophotometrically (288 nm) at ambient temperature, using a solution of known concentration of GH in the different media as a standard. To determine the solubility, a saturated solution was prepared by adding an excess of drug to 5ml of media. The solution was shaken in an orbital shaker for 24h. Then, the solution was centrifuged, supernatant was taken, suitably diluted and quantified for GH content using UV spectrophotometer at absorption maxima of 288nm^20–22.

In-vitro Drug Release Study:

The in vitro drug release study of GH pellets was performed using USP dissolution apparatus – II. Distilled water (900ml) was selected as dissolution media rotated at 50 rpm. The temperature was maintained at 37 ºC throughout the study. The aliquot of 10ml was withdrawn from the basket at predetermined time intervals and replaced with an equal volume of the fresh medium to maintain total volume constant. The sample was further suitably diluted, filtered through 0.45µm filter media and analyzed for GH content at 288nm wavelength using UV spectrophotometer (UV 1800, Shimadzu analytical Pvt. Ltd. India)²³,²⁴.

In vitro drug release kinetic study:

In vitro drug release data of optimized batch of GH pellets were analyzed by various mathematical models. The in vitro release data of GH in developed formulations and reference products was processed by using zero-order kinetics, first-order kinetics, Higuchi, Korsmeyer Peppas model, and the data obtained from all the time points was selected to simulate. The optimum values for the parameters present in each equation were determined by linear or non-linear least-squares fitting methods. Regression analysis was performed and the best fittings were calculated on the basis of the correlation coefficient as r ^25,26. Model-independent and dependent approach was briefly discussed below:

Model-Independent Approach:

Similarity Factor:

Similarity factor (f₂) and dissimilarity factor (f₁) are approved by the FDA for the comparison of drug release data of test to the reference formulation drug release data and is represented in equation 1 and 2 respectively. f₂has a value in the range of 50 to 100. If the value is 50-100, this shows similarity in the drug release profile of test to the standard. If the value was found to be less than 50, shows dissimilarity between the drug release profiles of test and reference²⁷.

Similarly, the f₁ dissimilarity factor is also widely used to compare the in vitro drug release profile of test to reference. If value ranges from 1 to 15, shows similarity in profile whereas value more than 15 suggests, dissimilarity in drug release profile of test and reference²⁷.

f₁ (Equation 1)

f₂ (Equation 2)

Where n is the sample number, and Rj and Tj are the percentages of the reference and test drug release, respectively, at different time intervals

Model Dependent Approach:

Zero-order release:

Zero-order release kinetics refers to the process of constant drug release from a drug delivery device such as oral osmotic tablets, transdermal systems, matrix tablets with low-soluble drugs and other delivery systems²⁸. In its simplest form, zero order release can be represented as:

Q = Q₀ + K₀t………………. (Equation 3)

Where, Q is the amount of drug released or dissolved (assuming that release occurs rapidly after the drug dissolves), Q₀ is the initial amount of drug in solution (it is usually zero), and K₀ is the zero order release constant. The plot made: cumulative % drug release vs. time (zero order kinetic model).

First-order release equation:

Many time drug release from dosage form show dependence on the concentration gradient (i.e. Cs - Ct) between the static liquid layer next to the solid surface and the bulk liquid. These considerations relate to conditions in which there is no change in the shape of the solid during the dissolution process (i. e. the surface area remains constant). However, for pharmaceutical tablets, disintegration occurs during the dissolution process and the surface area generated, therefore, varies with time. The plot made: log cumulative of % drug remaining vs. time (first-order kinetic model) and described by following equation,

ln (100-Q) = lnQ₀-k₁t……………………...(Equation 4)

Where, Q = the amount of drug release at time t, K₁=first order release constant

Higuchi square root of time equation:

Many controlled-release products are designed on the principle of embedding the drug in a porous matrix. Liquid penetrates the matrix and dissolves the drug, which then diffuses into the exterior liquid. Higuchi tried to relate the drug release rate to the physical constants based on simple laws of diffusion. The release rate from both a planar surface and a sphere was considered. The analysis suggested that in the case of spherical pellets, the time required to release 50% of the drug was normally expected to be 10% of the time required to dissolve the last trace of solid drug in the center of the pellet²⁸. Higuchi was the first to derive an equation to describe the release of a drug from an insoluble matrix as the square root of a time-dependent process based on Fickian diffusion²⁸.

Q = Kt^1/2…………………………………(Equation 5)

Where, Q = the amount of drug release at time t, K is the Higuchi square root of time release constant.

Korsmeyer and Peppas release mechanism:

Korsmeyer derived a simple relationship which described drug release from a polymeric system. To find out the mechanism of drug release, the first 60% drug release data were fitted in Korsmeyer–Peppas model²⁹,³⁰:

M_t

---- = Ktⁿ…………………………………(Equation 6)

M_α

Where, M_t/M_α is the fractional drug release at time t, K is the rate constant and n is the release exponent. The n value is used to characterize different release mechanisms for pellets.

The parameters in each equation were determined by using DD Solver software³¹. The correlation coefficient (R) was used to evaluate the applicability of these release models. The model with a maximum R-value was the best fit one²³.

Influence of hydro-alcoholic media on drug release:

The in vitro release tests were performed using USP apparatus ІІ (Paddle method). The Dissolution medium was distilled water and 0% or 10% or 20% or 30% or 40% alcohol maintained at 37 ± 0.5°C. The volume was kept 900ml and the paddle rotation speed was kept at 50 rpm³². In all experiments, an aliquot of 10 ml dissolution samples was withdrawn at predetermined time intervals and replaced with an equal volume of the fresh medium to maintain total volume constant. Samples will be filtered through the filter (0.45 µm) and assayed by UV spectrophotometry at 288 nm²⁶. For each medium, six tablets were tested and drug release was monitored spectrophotometrically. Concentrations of ethanol in the range of 0–40% v/v were studied whereby 0% is the control and 40% is that found in spirits³³.

Pellets were tested for two different conditions:

Condition A (Short time (1h) exposure to hydro-alcoholic media): In vitro drug release was performed for 1h in hydroalcoholic media and further transferred to non-alcoholic (dist. Water) media for 11h

Condition B (Long time (12 h) exposure to hydro-alcoholic media): In vitro drug release was performed for 12h in hydroalcoholic media i.e. extreme condition⁸,³⁴,³⁵

Alcohol is rapidly absorbed from the gastrointestinal tract (GIT) and is distributed throughout the body fluids. Number of factors like presence of food, type of food, alcohol concentration, disease condition, and time of ingestion of alcohol affect the absorption of alcohol from GIT. Oral solid dosage form generally comes in contact with alcohol maximum up to 12h considering all the factor influence. In reality, alcohol is absorbed in the GIT in 1h but here to assess the harsh condition, 12h exposure of pellets to alcohol was selected⁸. Therefore, in order to check the effect of hydro-alcoholic media on COM and EC containing GH pellets under the GIT simulating condition, the pellets were exposed to short (1h) as well as long period of time. The in vitro drug release data of hydro alcoholic media was compared to non-hydro-alcoholic media using similarity factor.

Data analysis:

The in-vitro drug release was fitted to following equation 7 to find out the drug release mechanism from the pellets.

---- = Q = Ktⁿ ……………………………(Equation 7)

Mα

Where, Q is the percentage drug released at time t, k is a kinetic constant incorporating structural and geometric characteristics of the tablet and n is the release exponent indicative of the drug release mechanism. Values of n approximating 0.5 indicate predominantly diffusion control and values approximating 1.0 correspond to zero-order release^8,23.

RESULT AND DISCUSSION:

Solubility study of Galntamine HBr:

The saturated solubility of GH was assessed in various hydro-ethanolic media as well as in pure methanol. The solubility data are shown in Table 2.

Table 2: Saturated solubility of the Galantamine HBr in different hydro-ethanolic media (mg/ml)

Medium	Saturated solubility in mg/ml
Distilled water	1.69±0.037
Ethanol	1.10±0.037
Distilled water + 10% ethanol	1.56±0.049
Distilled water + 20% ethanol	1.42±0.057
Distilled water + 30% ethanol	1.33±0.031
Distilled water + 40% ethanol	1.26±0.031

In vitro drug release:

All the design batches were evaluated for the in vitro drug release. The results of the in vitro drug release suggest that, as the concentration of polymers increases, the more drug release retardation was observed. The decrease in the drug release might be due to decrease in the porosity inside the pellets, leads to decrease in the penetration of dissolution media into the system, and reduces the drug solublization or dissolution. In addition to this, there may be increase in the path length for the diffusion of drug from matrix and ultimately leads to decrease drug release³⁶.

From the overlaid plot, the optimized batch was selected which shows desired drug release at the definite time interval. The optimized batch was compared with the marketed formulation. The f₂ value was found to be 77.03 which showed that both formulations’ drug profile is similar.

The data obtained from in vitro dissolution study of the optimized batch was applied to zero order, first order, Higuchi, Koresemeyer-Peppas equation to find out drug release mechanism from the matrix pellets. The zero-order rate equation described the system where the release rate was independent of the concentration of dissolved species. The first-order equation described the release from the system where dissolution rate was dependent on concentration of dissolved species. The Higuchi square root equation described the release from system where the solid drug was dispersed in the insoluble matrix, and rate of drug release was related to rate of drug diffusion³⁷. According to Peppas, if n value is 0.5 suggest Fickian diffusion and more than 0.5 suggest non-Fickian diffusion.

Best fit kinetic data with the highest value of regression coefficient was found with zero order, Higuchi and Korsmeyer-Peppas model as shown in Table 3. In Korsmeyer-Peppas, n value was found to be 0.5708 which shows non-Fickian diffusion. Non-fickian diffusion suggests that the drug is released by diffusion and polymer relaxation. The formulated GH pellets was also compared with the marketed formulation using similarity factor f_2.The f2 value was found to be 77.03 which show that the drug release profile of formulated pellets is similar to the drug release profile of marketed product.

CONCLUSION:

A robust formulation was developed containing COM and EC which showed that the in vitro drug release was not affected in the presence of alcohol. There was a slightly lower drug release was observed in the presence of the higher concentration of alcohol but it was due to the change of GH solubility in ethanol and not due to the failure of polymer matrices. Hydro-alcoholic media significantly affect the drug release kinetics and mechanism but not significantly affect the drug release. The controlled release GH pellets were successfully formulated which was not affected by alcohol even in worst condition using COM and EC incorporating extrusion spheronization technique.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Anand Pharmacy College, Anand for the facilities. The authors are also thankful to Zydus Research Centre, Ahmedabad, India, FMC Biopolymer (Philadelphia, PA, USA), Gattefossé India Pvt. Ltd., Mumbai, India, Dow Chemical International Pvt. Ltd., Mumbai, India for providing gift sample.

CONFLICT OF INTEREST:

The authors do not have any conflict of interest.

REFERENCES:

1. Lazzari A, Kleinebudde P, Knop K. Xanthan gum as a rate-controlling polymer for the development of alcohol resistant matrix tablets and mini-tablets. Int J Pharm [Internet]. 2018;536(1):440–9. Available from: http://dx.doi.org/10.1016/j.ijpharm.2017.12.014

2. Nep EI, Mahdi MH, Adebisi AO, Ngwuluka NC, Conway BR, Smith AM, et al. Hydro-alcoholic media effects on theophylline release from sesamum polysaccharide gum matrices. Drug Dev Ind Pharm [Internet]. 2018;44(2):251–60. Available from: https://doi.org/10.1080/03639045.2017.1386209

3. World Health Organization. Global status report on alcohol and health 2018 [Internet]. 2018. Available from: http://www.who.int/substance_abuse/publications/global_alcohol_report/en/

4. Robert J., Meyer M., Hussain A. FDA ’ s ACPS Meeting , Awareness Topic : Mitigating the Risks of Ethanol Induced Dose Dumping from Oral Sustained / Controlled Release Dosage Forms Ph . D . Office of New Drugs and Office of P. Center for Drug Evaluation and Research, FDA. 2005.

5. USFDA. FDA’s alert for healthcare professionals. Hydromorphone hydrochloride extended-release capsules (marketed as PalladoneTM), Alcohol- PalladoneTM interaction. [Internet]. Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm129288.htm

6. Nep EI, Mahdi MH, Adebisi AO, Dawson C, Walton K, Bills PJ, et al. The influence of hydroalcoholic media on the performance of Grewia polysaccharide in sustained release tablets. Int J Pharm [Internet]. 2017;532(1):352–64. Available from: http://dx.doi.org/10.1016/j.ijpharm.2017.09.022

7. Missaghi S, Fegely KA, Rajabi-Siahboomi AR. Investigation of the effects of hydroalcoholic solutions on textural and rheological properties of various controlled release grades of hypromellose. AAPS PharmSciTech [Internet]. 2009;10(1):77–80. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2663671&tool=pmcentrez&rendertype=abstract

8. Levina M, Vuong H, Rajabi-Siahboomi AR. The influence of hydro-alcoholic media on hypromellose matrix systems. Drug Dev Ind Pharm. 2007;33(10):1125–34.

9. Emeje M, Nwabunike P, Isimi C, Kunle O, Ofoefule S. Hydro-Alcoholic Media: An Emerging in vitro Tool for Predicting Dose Dumping from Controlled Release Matrices. J Pharmacol Toxicol. 2008;3(2):84–92.

10. Larsson M, Hjärtstam J, Berndtsson J, Stading M, Larsson A. Effect of ethanol on the water permeability of controlled release films composed of ethyl cellulose and hydroxypropyl cellulose. Eur J Pharm Biopharm [Internet]. 2010;76(3):428–32. Available from: http://dx.doi.org/10.1016/j.ejpb.2010.09.007

11. Muley S, Nandgude T, Poddar S. Extrusion – spheronization a promising pelletization technique : In-depth review. Asian J Pharm Sci [Internet]. 2016;11(6):684–99. Available from: http://dx.doi.org/10.1016/j.ajps.2016.08.001

12. Roy P, Shahiwala A. Multiparticulate formulation approach to pulsatile drug delivery : Current perspectives. J Control Release [Internet]. 2009;134(2):74–80. Available from: http://dx.doi.org/10.1016/j.jconrel.2008.11.011

13. Fakult M, Petrovick GF. Orodispersible Tablets Containing Taste- Masked Lipid Pellets with Metformin Hydrochloride for Use by Elderly Patients [Internet]. Heinrich-Heine-Universität Düsseldorf; 2015. Available from: https://docserv.uni-duesseldorf.de/servlets/DerivateServlet/Derivate-36734/Doctoral Thesis Petrovick.pdf

14. Patere SN, Kapadia CJ, Nagarsenker MS. Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol(®) 888ATO as Lipid Excipient. Indian J Pharm Sci [Internet]. 2015;77(5):620–5. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4700717&tool=pmcentrez&rendertype=abstract

15. Marchaud D, Cuppok Y, Arcuri K, Girard JM, Miolane C. Improving drug safety : Compritol ® 888 ATO matrix tablets deliver consistent sustained drug release in hydro-alcoholic media and when broken . :1–2.

16. Crowley MM, Schroeder B, Fredersdorf A, Obara S, Talarico M, Kucera S, et al. Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion. Int J Pharm. 2004;269(2):509–22.

17. Singh G, Pai RS, Devi VK. Optimization of Pellets Containing Solid Dispersion Prepared by Extrusion / Spheronization Using Central Composite Design and Desirability Function. J Young Pharm [Internet]. 2012;4(3):146–56. Available from: http://dx.doi.org/10.4103/0975-1483.100020

18. Wang J, Kan S, Chen T, Liu J. Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion-spheronization. Pharm Dev Technol [Internet]. 2015;20(2):246–56. Available from: http://dx.doi.org/10.3109/10837450.2014.908300

19. Rana HB, Gohel MC, Dholakia MS, Gandhi TR, Omri A, Thakkar VT. Development of Sustained Release Pellets of Galantamine HBr by Extrusion Spheronization Technique Incorporating Risk based QbD Approach. Res J Pharm Technol. 2018;11.

20. Zhang L, Huang Z, Wan X, Li J, Liu J. Measurement and Correlation of the Solubility of Febuxostat in Four Organic Solvents at Various Temperatures. J Chem Eng Data. 2012;57:3149–52.

21. Patel A V, Patel VJ, Patel A V, Dave JB, Patel CN. Determination of galantamine hydrobromide in bulk drug and pharmaceutical dosage form by spectrofluorimetry. J Pharm Bioallied Sci. 2013;5(4):314–7.

22. Roberts M, Cespi M, Ford JL, Dyas AM, Downing J, Martini LG, et al. Influence of ethanol on aspirin release from hypromellose matrices. Int J Pharm [Internet]. 2007;332(1–2):31–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0378517306007903

23. Yan H, Zhang S, He J, Liu J. Application of ethyl cellulose, microcrystalline cellulose and octadecanol for wax based floating solid dispersion pellets. Carbohydr Polym [Internet]. 2016;148:143–52. Available from: http://dx.doi.org/10.1016/j.carbpol.2016.04.050

24. Galantamine Extended-Release Capsules, USP Revision Bulletin Official. 2016.

25. Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm [Internet]. 2010;67(3):217–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20524422

26. Yang S. Preparation and evaluation of novel galantamine hydrobromide sustained-release capsule. Bangladesh J Pharmacol. 2016;11:82–91.

27. Gohel MC, Sarvaiya KG, Mehta NR, Soni CD, Vyas VU, Dave RK. Assessment of similarity factor using different weighting approaches. Dissolution Technol. 2005;12(4):22–7.

28. Singhvi G, Singh M. Review : in-Vitro Drug Release Characterization Models. Int J Pharm Stud Res. 2011;II(I):77–84.

29. Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose ( HPMC ). Adv Drug Deliv Rev [Internet]. 2012;64:163–74. Available from: http://dx.doi.org/10.1016/j.addr.2012.09.028

30. Korsmayer RW, Gumy R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. interantional jouranl Pharm. 1983;15:25–35.

31. Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DDSolver: An Add-In Program for Modeling and Comparison of Drug Dissolution Profiles. AAPS J [Internet]. 2010;12(3):263–71. Available from: http://www.springerlink.com/index/10.1208/s12248-010-9185-1

32. Jedinger N, Schrank S, Mohr S, Feichtinger A, Khinast J, Roblegg E. Alcohol dose dumping: The influence of ethanol on hot-melt extruded pellets comprising solid lipids. Eur J Pharm Biopharm [Internet]. 2015;92:83–95. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-84924764680&partnerID=tZOtx3y1

33. Fadda HM, Mohamed MAM, Basit AW. Impairment of the in vitro drug release behaviour of oral modified release preparations in the presence of alcohol. Int J Pharm [Internet]. 2008;360(1–2):171–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0378517308003426

34. Levina M, Rajabi-siahboomi AR. The influence of concomitant use of alcoholic beverages on hypromellose matrix tablets. Pharm Technol [Internet]. 2008;20(12):1–4. Available from: http://www.pharmtech.com/influence-concomitant-use-alcoholic-beverages-hypromellose-matrix-tablets

35. Palmer D, Levina M, Farrell TP, Rajabi-siahboomi A. The Influence of Hydro-Alcoholic Media on Drug Release from Polyethylene Oxide Extended Release Matrix Tablets. Pharm Technol. 2011;35(7):1–8.

36. Dhameliya P. Preparation and evaluation of sustained release tablet of eperisone hydrochloride by Compritol ATO 888 as a matrix forming agent. J Drug Deliv Ther. 2014;4(3):132–7.

37. Angadi SC, Manjeshwar LS, Aminabhavi TM. Stearic acid-coated chitosan-based interpenetrating polymer network microspheres: Controlled release characteristics. Ind Eng Chem Res. 2011;50(8):4504–14.

Received on 29.09.2018 Modified on 16.10.2018

Research J. Pharm. and Tech 2019; 12(2):791-798.

DOI: 10.5958/0974-360X.2019.00138.0

Model	Zero-order	First-order	Higuchi	Korsmeyer- Peppas		f₂Value
Batches	r²	r²	r²	r²	n Value
Optimum Batch	0.9181	0.8050	0.9791	0.9889	0.5708	77.03
Marketed formulation	0.9012	0.7892	0.9698	0.9808	0.5158	--

Dissolution testing condition	Exposure to 1h to ethanol followed by 11h in distilled water (Short exposure)			Exposure to 12h to ethanol (Long exposure)
Dissolution testing condition	n value	K value	r² value	n value	K value	r² value
0% ethanol	0.5708	3.50	0.9889	0.5708	3.56	0.9889
10% ethanol	0.6010	3.44	0.9707	0.6005	3.03	0.9760
20% ethanol	0.6102	3.38	0.9624	0.6101	2.94	0.9527
30% ethanol	0.6205	3.16	0.9933	0.6210	2.90	0.9661
40% ethanol	0.6445	2.88	0.9393	0.6332	2.86	0.9792