Sustained Release Tablets Thesis Statements

Abstract

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

Keywords: Eudragit RSPO, gum copal, gum damar, matrix tablets, release kinetics

Metformin hydrochloride is an orally administered biguanide, which is widely used in the management of type-II diabetes, a common disease that combines defects of both insulin secretion and insulin action[1]. Unlike other antidiabetic drugs metformin HCl does not induce hypoglycemia at any reasonable dose, and hence it is called as an antihyperglycaemic rather than a hypoglycemic drug[2]. It is a hydrophilic drug and is slowly and incompletely absorbed from the gastrointestinal tract, and the absolute bioavailability is reported to be of 50-60 %[3,4]. An obstacle to more successful use of metformin therapy is the high incidence of concomitant gastrointestinal symptoms, such as abdominal discomfort, nausea, and diarrhea that especially occurs during the initial period of treatment. The compound has relatively short plasma half-life of 1.5-4.5 h and the low absolute bioavailability of 50-60 %[5]. Side effects, short half lives, low bioavailability and the need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. Matrix systems are widely used in oral controlled drug delivery because of their flexibility, cost effectiveness, low influence of the physiological variables on its release behavior and broad regulatory acceptance[6,7]. Many researchers investigated various natural, semi-synthetic and synthetic polymeric materials. Cellulose ethers such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, Eudragit (polymethacrylate) polymer[8,9], ethyl cellulose[10] and some natural gums like guar gum and xanthan gum are widely used hydrophilic polymers as release retardants[11].

Methacrylic resins (Eudragit) appear particularly attractive due to their high chemical stability and compactility properties, and many literatures substantiate use in the development of control release matrix tablet[12,13]. The hydrophilic polymer selected for the present study was Eudragit RSPO, which provide pH-independent drug release to oral dosage forms that can be used for formulating the sustained-release dosage forms[14]. However, the use of hydrophilic matrix alone for extending drug release for highly water soluble drugs is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. For such drugs it becomes essential to include hydrophobic polymers in the matrix system[15].

The natural materials have been extensively used in the field of drug delivery because they are readily available, cost-effective, eco-friendly, capable of multitude of chemical modifications, potentially degradable and compatible due to their natural origin[16]. Gum copal (GC) and gum damar (GD) are natural resinous materials of plant Bursera bipinnata family Burseraceae and Shorea wiesneri family Dipterocarpaceae, respectively. The wide applications of GC and GD propose their strong hydrophobic nature, substantial binding property, compatibility with the physiologic environment[17] and their sustaining property[18]. The objective of this work was to prepare sustained release metformin HCl matrix tablets using synthetic hydrophilic polymer eudragit RSPO alone or in combination with hydrophobic natural polymer, GC and GD to evaluate the in vitro release characteristic and to predict and correlate the release behavior of metformin HCl from the matrices. The influence of the polymer concentration in the tablets was also investigated. The in vitro drug release profiles of the matrices are evaluated, and its release mechanism was studied.

Although Eudragit RSPO has been widely used as sustained release material; to our knowledge the property of its combination with GC and Gd has not been evaluated. Hence, in the present work, an attempt has been made to formulate the extended-release matrix tablets of metformin HCl using hydrophilic polymer Eudragit RSPO alone or in combination with hydrophobic natural polymer, GC and GD to evaluate the in vitro release characteristics and to predict the release behavior.

MATERIALS AND METHODS

Metformin HCl was obtained from Universal Medicament Nagpur, India. Microcrystalline cellulose (MCC, Avicel pH 101) and ethyl cellulose were purchased from S. D. Fine Chem. Labs. (Mumbai, India), Eudragit RSPO (ammonium meth acrylic copolymer type A NF) was obtained as gift samples from Degussa India Ltd. (Mumbai, India), and gum copal and gum damar were received as a gift sample from Imex Inc. (Chennai, India). All other ingredients used throughout the study were of analytical grade and were used as received.

Study of physical interaction between drug and polymer:

Infrared spectrum was taken by scanning the samples of pure drug and the polymers individually over a wave number range of 4000 to 400 cm-1 using Fourier transform infrared spectrophotometer (FT-IR, Shimadzu 8400S, Shimadzu, Japan). The change in spectra of the drug in the presence of polymer was investigated which indicates the physical interaction of drug molecule with the polymer.

Preparation of Metformin hydrochloride matrix tablets:

Matrix tablets, each containing 500 mg metformin HCl were prepared by a conventional non-aqueous wet granulation technique. The composition of various formulations of the tablets with their codes is listed in Table 1. The composition with respect to polymer combination was selected on the basis of trial preparation of tablets. In each formulation, the amount of the active ingredient is 500 mg and the total weight of a tablet is 1000 mg. A batch of 30 tablets was prepared with each formula. The ingredients were passed through a 60-mesh sieve. A blend of all ingredients except glidant and lubricant was mixed, a particular attention had been given to ensure thorough mixing and phase homogenization. Granulation was done manually with a solution of isopropyl alcohol. The wet masses were passed through a 12 mesh sieve and the wet granules produced were first air dried for 10 min and finally at 45-50° in a tray drier for 2 h. The dried granules were sized by a 16-mesh sieve and after lubrication with magnesium stearate. Compression was carried out using 14 mm flat faced circular punches into tablets on an eight station rotary press tablet compression machine (Rimek Minipress I Ahmadabad, India) at a constant compression force. Just before compression, the surfaces of the die and punches were lubricated with magnesium stearate. All the tablets were stored in airtight containers for further study. Prior to compression, granules were evaluated for their flow and compressibility characteristics.

TABLE 1

COMPOSITION OF VARIOUS TRIAL FORMULATIONS PREPARED

Evaluation of granules:

The granules were evaluated for angle of repose, loose bulk density (LBD), tapped bulk density (TBD), compressibility index and drug content. Angle of repose was determined by funnel method. Bulk density and tapped density were determined by cylinder method, and Carr's index (CI) was calculated using the following equation. Carr's index=(TBD-LBD)×100/TBD. Hausner's ratio was related to interparticle friction and could be used to predict powder flow properties. Hausner's values of the prepared granules ranged from 1.12 to 1.25 was thought to indicate good flow properties[19].

Evaluation of tablets:

The prepared matrix tablets were evaluated for hardness, weight variation, thickness, friability and drug content[19]. Hardness of the tablets was tested using a Strong-Cobb hardness tester (Tab-machine, Mumbai, India). Friability of the tablets was determined in a Roche friabilator (Campbell Electronics, Mumbai, India). The thickness of the tablets was measured by vernier caliper. Weight variation test was performed according to the official method[20]. Drug content was analyzed by measuring the absorbance of standard and samples at λ=233 nm using UV/Vis spectrophotometer (Shimadzu 1601, Kyoto, Japan).

In vitro drug release studies:

Drug release studies were conducted using USP-22 dissolution apparatus-2, paddle type (Electrolab, Mumbai, India) at a rotational speed of 50 rpm at 37±0.5°. The dissolution media used were 900 ml of 0.1 mol/l HCl for first 2 h followed by pH 6.8 phosphate buffer solution for 12 h. Sink condition was maintained for the whole experiment. Samples (10 ml) were withdrawn at regular intervals and the same volume of pre-warmed (37±0.5°) fresh dissolution medium was replaced to maintain the volume constant. The samples withdrawn were filtered through a 0.45 μ membrane filter (Nunc, New Delhi, India) and the drug content in each sample was analyzed after suitable dilution with a UV spectrophotometer (Shimadzu UV-1700) at 233 nm[21]. The dissolution test was performed in triplicate. Drug dissolved at specified time periods was plotted as cumulative percent release versus time (h) curve.

Kinetic Analysis of release data:

The release data obtained were treated according to zero-order (R=k1t), first-order (R=k1t), Higuchi (R=k3√t )[22], Korsmeyer-Peppas (log R=log k4+n log t) equation, Hixson–Crowell equations ((UR)1/3= k5t)[23] to find the equation with the best fit. Where R and UR are the released and unreleased percentages, respectively, at time (t); k1, k2, k3, k4, and k5 are the rate constants of zero-order, first-order, Higuchi matrix, Peppas-Korsmeyer, and Hixon-Crowell model, respectively. In order to compare the release profile of different formulas with possible difference in release mechanisms (n values), a mean dissolution time (MDT)[14] was calculated using Eq. MDT=(n/n+1).K-1/n, Where n = release exponent and K= release rate constant.

Statistical Analysis:

The data was subjected to two ways ANOVA followed by Bonferroni post test for analyzing the statistical difference using the software GraphPad Prism (San Diego, CA) and in all the cases P < 0.001 was considered as significant.

RESULTS AND DISCUSSION

FTIR studies revealed that metformin HCl showed two typical bands at 3369 and 3283 cm-1 due to N-H primary stretching vibration and a band at 3170 cm-1 due to N-H secondary stretching and characteristics bands at 1623 and 1560 cm-1 assigned to C=N stretching. No significant change in the appearance of characteristic peaks of pure drug spectra was observed (fig. 1). This indicates that the drug is compatible with the polymers used in the investigation.

The granules of proposed formulations were evaluated for LBD, TBD, Compressibility index, angle of repose and Hausner's ratio (Table 2). An angle of repose of less than 30 degrees indicates good flow properties. This was further supported by the lower compressibility index. Granules with Carr's index values around 21% and below are considered to have fair and excellent flow properties[19].

TABLE 2

PHYSICAL PROPERTIES OF THE GRANULES

Table 3 gives the physical parameters such as hardness, thickness, friability and weight uniformity of all the fabricated tablets. All the tablets of different formulations showed acceptable results with respect to weight variation, drug content uniformity, friability. All formulations showed less than 1% (w/w) friability, which was within the prescribed limits[24]. According to the Pharmacopoeial recommendation for tablets weighing more than 324 mg, ±5% deviation from the mean weight is acceptable[20]. As the results show, the average weight deviation percentage of 20 tablets taken from each formulation was less than ±0.5%, and all the formulations met the requirement. The manufactured tablets showed low weight variations and a high degree of drug content uniformity among different batches of the tablets, and drug content was more than 95%.

TABLE 3

PHYSICAL PROPERTIES OF THE MATRIX TABLETS

The results of dissolution studies of formulations F-I, F-II, and F-III, composed of eudragit RSPO (20, 30 and 40%) are shown in fig. 2. Tablets F-I, F-II and F-III released 43.88, 47.37 and 48.64% of metformin HCl at the end of 2 h; and 92.35, 92.73, and 93.69% of drug at the end of 8 h., respectively. No significant difference (P<0.001) in release rate was observed between tablets containing either 30 or 40% of Eudragit RSPO (92.35, 92.73% at 8 h). Further increase in concentration of Eudragit did not significantly (P<0.001) affect the release rate. On this basis, 30% of Eudragit RSPO was selected for further studies.

Fig. 2

In vitrocumulative release of metformin.

The results of dissolution studies of formulations F-IV, F-V, and F-VI, composed of GC (20, 30 and 40%) are shown in fig. 3. Tablets F-IV, F-V, and F-VI, released 41.19, 40.11 and 40.47% of metformin HCl at the end of 2 h; and 90.72, 88.56 and 83.12% of drug at the end of 10 h, respectively. Formulations F-VII, F-VIII, and F-IX, composed of GD (20, 30 and 40%) are shown in fig. 4. Tablets F-VII, F-VIII, and F-IX, released 43.61, 46.36 and 36.73% metformin HCl at the end of 2 h; and 93.53, 92.22 and 90.77% of drug at the end of 10 h, respectively. The results of dissolution studies of formulations F-X, F-XI, and F-XII, composed of combination of Eudragit RSPO and GC (75:25, 50:50 and 25:75% respectively) are shown in fig. 5. Tablets F-X, F-XI, and F-XII, released 31.62, 29.39 and 28.60% metformin HCl at the end of 2 h; and 96.96, 93.52 and 90.66% of drug at the end of 12 h, respectively. The results of dissolution studies of formulations F-XIII, F-XIV, and F-XV composed of combination of Eudragit RSPO and GD (75:25, 50:50 and 25:75%, respectively) are shown in fig. 6. Tablets - F-XIII, F-XIV, and F-XV, released 31.36, 30.96 and 28.89% of metformin HCl at the end of 2 h; and 95.16, 91.83, and 89.71% of drug at the end of 12 h, respectively. As indicated in fig. 2, tablets containing Eudragit RSPO (20, 30 and 40%) alone showed initial burst release during first hour (31.32, 33.14 and 37.47%, respectively). Eudragit RSPO contains quaternary ammonium groups, and solubilization of these quaternary ammonium groups in acidic pH leads to formation of pores in the matrix, thereby releasing metformin HCl in the acidic pH. This phenomenon may be attributed to surface erosion or initial disaggregation of the matrix tablet prior to gel layer formation around the tablet core[25].

Fig. 3

In vitro cumulative release of metformin.

Fig. 4

In vitro cumulative release of metformin.

Fig. 5

In vitro cumulative release of metformin.

Fig. 6

In vitro cumulative release of metformin.

Metformin HCl release profile of GC and GD matrix tablets is shown in fig. 2 and fig. 3, respectively. As regards the effect of gum concentration, decrease in drug release rate was observed when GC and GD content in the matrix were increased. This may be due to the reason that the gums in higher concentrations in the tablets might have produced dense matrix around the drug particles, providing more barriers for them to escape and dissolve. Further, such dense matrix, specifically when it is hydrophobic in nature, may be expected to favor less penetration of the dissolution medium in the tablets. This may also be the auxiliary reason for obtaining slow drug release profiles through GC and GD matrix tablets. In low concentrations (10% w/w), GC showed significant sustained drug delivery compared to GD. Tablets with 20% w/w GC and GD showed 85.56%, and 90.83% total drug release at the end of 10 h respectively. This may be due to the low solubility of GC compared to GD at pH 1.2 and pH 6.8. Both the gums in 30% w/w concentration retarded metformin HCl release beyond 10 h. Drug release from GC and GD matrix followed zero order and Higuchi square root kinetics respectively.

In formulations containing combinations of hydrophilic and hydrophobic polymers, FX, FXI, FXII, (fig. 5) and F-XIII, F-XIV, F-XV (fig. 6), showed a significant difference (P<0.001) of drug release as compared with 10 and 20% of either of the Eudragit preparation. Hydrophilic eudragit when combined with hydrophobic GC and GD (FX-FXV) no burst release was observed, which may be due to the tendency to mask these quaternary ammonium groups to some extent, thereby modifying release of the drug. It is reported in the literature that more than 30% release of drug in the first hour of dissolution indicates the chance of dose dumping. The results showed probability of dose dumping from matrix tablets prepared without GC and GD.

To describe the kinetics of drug release from matrix tablets, release data was analyzed according to different kinetic equations. The data were analyzed by the regression coefficient method and regression coefficient values (r2) of all batches were shown in Table 4. On analyzing regression coefficient values of all batches, it was found that Batch F-I, II, III tablet exhibited almost zero-order kinetics. Batch F-IV, F-V, F-VI, F-VII and F-VIII tablet followed Higuchi model, whereas Batches F-IX, F-X, F-XI, and F-XII tablet followed first order kinetics.

TABLE 4

IN VITRO RELEASE KINETICS PARAMETERS

The in vitro release profiles of drug from all these formulations could be best expressed by Higuchi's equation as the plots showed highest linearity (r2 =0.98 to 0.99)[22]. To confirm the diffusion mechanism, the data were fitted into Korsmeyer-Peppas equation[23]. The formulations showed good linearity (r2 =0.97 to 0.98) with slope (n) between 0.477-0.5879, which appears to indicate a coupling of diffusion and erosion mechanisms-so called anomalous diffusion.

The time taken to release 25% (t25), 50% (t50), and 75% (t75) of drug from different formulations was determined (Table 5). Tablets containing combination of Eudragit RSPO with GC (F-X, XI and F-XIII) required 1.6, 0.9, 1.4 h and 6.6, 7.9 and 8.5 h to release 25% and 75% of drug, respectively. While combination of Eudragit RSPO with GD (F-XIV, XV and F-XVI) required 1.4, 1.8, 1.4 h and 7.1, 7.4 and 8.4 h to release 25% and 75% of drug, respectively. These values were significantly higher than those obtained in matrix tablets formulated with either Eudragit RSPO or GC and GD alone, which clearly indicated sustained release nature of the combination of both Eudragits with GC and GD.

TABLE 5

IN VITRO DISSOLUTION PARAMETERS

Mean dissolution time (MDT) value is used to characterize drug release rate from a dosage form and indicates the drug release retarding efficiency of polymer. Tablets prepared with combination of Eudragit RSPO with GC and GD (F-X, F-XI, F-XII and F-XIII, F-XIV, F-XV) showed higher MDT value (3.98, 4.11, and 4.45 h; 3.97, 4.19 and 4.28, respectively). This finding can be attributed to the hydrophobic nature of GC and GD, which retarded drug release from the matrix.

The synthetic hydrophilic matrix of Eudragit RSPO alone could not sustain the release of the metformin HCl effectively for 12 h. Results of the present study demonstrated that combination of both synthetic hydrophilic (Eudragit RSPO) with natural hydrophobic polymers (GC and CD) could be successfully employed for formulating sustained-release matrix tablets. Diffusion coupled with erosion might be the mechanism for the drug release from hydrophilic and hydrophobic polymer based matrix tablets which can be expected to reduce the frequency of administration and decrease the dose-dependent side effects associated with repeated administration of conventional metformin HCl Tablets.

ACKNOWLEDGMENTS

The authors thank the Universal Medicament, Nagpur, India for providing Metformin HCl as gift sample and S. K. B. College of Pharmacy, Kamptee, Nagpur, India for providing necessary facilities to carry out this work.

Footnotes

Wadher, et al.: Sustained Release Metformin Hydrochloride Tablets

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CONTENTS

CHAPTER 1: INTRODUCTION
1.1 Introduction
1.2 Historical viewpoints of controlled release drug delivery
1.3 Sustained release drug delivery system
1.3.1 Concept of sustained release drug delivery system
1.3.2 Rationale of sustained release drug delivery system
1.3.3 Oral sustained release drug delivery system
1.3.4 Advantages of sustained release dosage forms
1.3.5 Disadvantages of sustained release dosage forms
1.3.6 Drugs unsuitable for sustained release dosage forms
1.3.7 Factors affecting sustained release dosage forms
1.3.7.1 Physicochemical properties of the drug affecting sustained release dosage forms
1.3.7.2 Biological properties of the drug affecting sustained release dosage forms
1.3.8 Formulation methods used to prepare sustained release dosage forms
1.3.8.1 Particle size modification
1.3.8.2 Matrix system
1.3.8.3 Coating system
1.3.8.4 Beads and sphere
1.3.8.5 Enteric coated beads in capsule
1.3.8.6 Mixed release granules
1.3.8.7 Repeated action tablets
1.3.8.8 Erosion core with initial dose
1.3.8.9 Erosion core only
1.3.8.10 Ion exchange resin
1.3.8.11 Complexation
1.3.8.12 Microencapsulation
1.3.8.13 The osmotic tablet
1.3.8.14 Gel forming hydrocolloids
1.3.8.15 Environmentally responsive system
1.3.9 Methods and mechanisms of sustaining drug action
1.3.9.1 Diffusional systems
1.3.9.2 Dissolution controlled system
1.3.9.3 Water penetration controlled system
1.3.9.4 Chemically controlled systems
1.3.9.5 Hydrogels
1.3.9.6 Ion exchange resins
1.3.10 Technical sophistication based classification of sustained release drug delivery
1.4 Matrix devices
1.4.1 Polymers used in matrix devices
1.4.2 Properties of an ideal polymer
1.4.3 Classification of polymers
1.4.3.1 Matrix devices with insoluble inert polymer
1.4.3.2 Matrix devices with insoluble erodible polymer
1.4.3.3 Matrix devices with hydrophilic polymer
1.4.3.4 Matrix devices with hydrogel polymer
1.4.4 Use of excipients in matrix devices
1.4.5 Release mechanisms from matrices
1.4.6 Mathematical models of release mechanics from matrices
1.4.6.1 Release from soluble retardants
1.4.6.2 Release from insoluble retardants
1.4.6.3 Drug release of low solubility in eluting media
1.4.6.4 Exponential model
1.4.6.5 Geometric dependence of diffusion exponent (n) and variation of n values with mechanism of diffusion
1.5 Thesis topic
1.5.1 Rationale
1.5.2 Active component
1.5.3 Physico-chemical properties of Nitroglycerin
1.5.4 Mechanism of action
1.5.5 Therapeutic use
1.5.6 Therapeutic dose
1.5.7 Contraindications
1.5.8 Pharmacokinetics
1.5.9 Pharmacology and toxicology
1.5.9.1 Mode of action
1.5.9.2 Interactions
1.5.9.3 Nitrate tolerance
1.5.10 Clinical effects
1.5.10.1 Acute poisoning
1.5.10.2 Chronic poisoning
1.5.11 Management of clinical effects
1.5.12 Decontamination

CHAPTER 2 : MATERIALS AND METHODS
2. Materials and methods
2.1 Materials
2.2. Drug profile
2.3. Excipients profile
2.3.1 Methocel
2.3.1.1 Nomenclature
2.3.1.2 Chemistry
2.3.1.3 Degree of substitution
2.3.1.4 Properties of Methocel K15M CR and Methocel K100LV CR
2.3.2 Profile of colloidal Silicon Dioxide (Aerosil 200)
2.3.3 Profile of Magnesium Stearate
2.4 Methods of study
2.4.1 Preparation of matrix tablet
2.4.2 Formulation of Nitroglycerin matrix tablet (F-1 – F-9)
2.5 Characterization of Nitroglycerin matrix tablets
2.5.1 Evaluation of physical properties of formulation granules
2.5.1.1 Bulk density
2.5.1.2 Compressibility index
2.5.1.3 Total porosity
2.5.1.4 Pharmacology and toxicology
2.5.1.5 Moisture content
2.5.1.6 Flow properties
2.5.1.7 Assay
2.5.2 Evaluation of physical properties of matrix tablet
2.5.2.1 Weight variation test
2.5.2.2 Hardness
2.5.2.3 Friability
2.5.2.4 Surface area
2.5.2.5 Moisture content
2.5.3 Chemical assay of Nitroglycerin in matrix tablets
2.5.3.1 Uniformity of content of active Nitroglycerin
2.5.3.2 Assay of Nitroglycerin after preparation of tablets
2.5.3.3 Assay of Nitroglycerin after 1 Month at 40°C + 75%RH
2.5.4 In-vitro release studies of Nitroglycerin matrix tablet
2.5.4.1 In-vitro dissolution medium
2.5.4.2 In-vitro dissolution studies of the tablet matrix
2.5.5 In-vitro release kinetic models
2.5.5.1 Zero order equation
2.5.5.2 First order equation
2.5.5.3 Higuchi square root law
2.5.5.4 Korsmeyer-Peppas model
2.5.5.5 Hixson-Crowell cube root law
2.5.6 Successive fractional dissolution time

CHAPTER 3: RESULTS AND DISCUSSION
3. Results and discussion
3.1 Evaluation of physical properties of Nitroglycerin granules
3.2 Evaluation of physical properties of Nitroglycerin tablets
3.3 Assay of Nitroglycerin matrix tablet
3.3.1 Uniformity of content of active Nitroglycerin
3.3.2 Assay of Nitroglycerin in the matrix tablet
3.3.3 Assay of Nitroglycerin after 1 Month at 40°C+75%RH in the matrix tablet
3.4 In-vitro dissolution and kinetic studies of Nitroglycerin matrix tablet in formulations (F–1 to F–9)
3.4.1 Effect of Methocel K15M CR (25%,20%,15%) and Methocel K100LV CR (15%,10%,5%) on release pattern of Nitroglycerin Matrix tablet
3.4.1.1 Zero order plot
3.4.1.2 First order plot
3.4.1.3 Higuchi plot
3.4.1.4 Korsmeyer-Peppas plot
3.4.1.5 Hixson-Crowell plot
3.4.2 Interpretation of release rate constant and R-square values for different release kinetics of (F–1 to F–9)
3.4.3 The best fitted model and mechanism of drug release from the matrix tablet of Nitroglycerin
3.4.4 Successive fractional dissolution time
3.5 Discussion about formulations (F–1 to F–9)

CHAPTER 4: CONCLUSION
4 Conclusion

CHAPTER 5: BIBLIOGRAPHY
5 Bibliography

FIGURES

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TABLES

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ACKNOWLEDGEMENT

I have great pleasure to acknowledge with sincere appreciation and a deep sense of gratitude to reverend teacher and supervisor Dr. Abu Shara Shamsur Rouf, Professor, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh, for his hearty co-operation, keen interest, excellent laboratory technical support and constant guidance to this work and also for his continuous constructive suggestions during the preparation of the manuscript of the thesis.

I am also highly obliged to all the honorable teachers of Department of Pharmaceutical Technology, University of Dhaka for their kind cooperation.

I also express my heartfelt felicitation to ACI Pharmaceutical Limited, for endless support with instruments, reagents and other accessories.

I extend my sincerest thanks especially to Mr. A. K. Lutful Kabir, Assistant Professor, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, and Ms. Sharifa Sultana, Lecturer, Department of Pharmacy, Daffodil International University Dhaka, Bangladesh, for their continuous suggestions and help during this work and the preparation of the manuscript of the project.

I also extend my sincerest thanks to all my friends, classmates, and senior brothers & sisters and well-wishers especially Shimul Halder, Shahidul Islam, Mizanur Rahman, Anwar Chowdhury, Abdullah Al Masud, Helal and Saiful.

ABSTRACT

The aim of the present studies was to develop and characterize 2.6 mg sustained release matrix tablets of Nitroglycerin. Tablets were prepared by direct compression method. Methocel K15M CR and Methocel K100LV CR polymers were used as rate retarding agents in nine formulations (F-1 to F-9). The granules were evaluated for angle of repose (26.78±0.01 to 29.25±0.030), loose bulk density (0.423±0.06 to 0.447±0.01gm/ml), tapped bulk density (0.516±0.02 to 0.544±0.04 gm/ml), Carr’s index (14.203±0.03 to 20.857±0.04%), Hausner ratio (1.166±0.01 to 1.264±0.03), moisture content (2.8879 to 3.4502%), total porosity (13.58±0.01 to 17.65±0.06%) and assay (2.593 to 2.721 mg/tablet). The tablets were subjected to diameter (8.0 mm), thickness (3.84±0.02 to 4.30±0.01 mm), assay (2.57 to 2.65 mg/tablet), uniformity of content (2.59±0.02 to 2.68± 0.02 mg/tablet), assay after 1Month at 40°C+75%RH (2.57±0.03 to 2.64±0.03 mg/tablet), hardness (8.0±0.06 to 8.9±0.06 kp), friability (0.11 to 0.49%) and in vitro dissolution studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with pharmacopoeial specifications for tested parameters. The in vitro dissolution study was carried out for 8 hour using USP-2009 Apparatus-I (Rotating basket method) in distilled water as the dissolution medium. The release mechanisms were explored and explained by Zero order, First order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell equations. Nine formulations were prepared by using three variable ratio of two polymers; Methocel K15M CR (25%, 20%, and 15%) and Methocel K100LV CR (15%, 10%, and 5%) where all the formulations (F-1 to F-9) contained 0.5% colloidal silicon dioxide and 1% magnesium stearate. Among these nine formulations, six formulations; F-2 (Methocel K15M CR: Methocel K100LV CR = 25% : 10%), F-3 (Methocel K15M CR : Methocel K100LV CR = 25% : 5%), F-4 (Methocel K15M CR : Methocel K100LV CR = 20% : 15%) F-5 (Methocel K15M CR: Methocel K100LV CR = 20% : 10%), F-6 (Methocel K15M CR : Methocel K100LV CR = 20% : 5%) and F-7 (Methocel K15M CR : Methocel K100LV CR = 15% : 15%) met the official specification of release profile. It was also found that the type and the amount of polymers significantly affect the time required for 50% (T50% or MDT) of drug release, release rate constant and diffusion exponent. Higher the MDT value indicates a higher drug retaining capacity of the polymers and vice-versa. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism of all proposed formulations followed anomalous type or non-Fickian transport (n>0.43 and n<0.85). These studies explored both of the optimum concentration and effect of polymers on Nitroglycerin release pattern from the tablet matrix for 8 hour period.

CHAPTER: ONE INTRODUCTION

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1.1. Introduction

A drug is a chemical substance used in the diagnosis, treatment or prevention of a disease and it should be recognized or defined by the U.S. Food, Drug, and Cosmetic Act (www.thefreedictionary.com/drug). Drugs are rarely administered as pure chemical substances alone rather these are almost always given as formulated preparations or medicines. These can vary from relatively simple solutions to complex drug delivery systems through the use of appropriate excipients in the formulations.

The principal object of dosage form design is to achieve a predictable therapeutic response to a drug included in a formulation which is capable of large scale manufacture with reproducible product quality. To ensure product quality, numerous features are required-

- Chemical and physical stability
- Uniformity of dose of drug
- Suitable preservation against microbial contamination
- Acceptability to user including both prescriber and patient
- Suitable packaging and labeling.

Before a drug substance can be successfully formulated into a dosage form many factor must be considered. These can be broadly grouped into three categories:

1. Biopharmaceutical considerations, including absorption, distribution, metabolism and excretion of drug;
2. Drug factor, such as the physical and chemical properties of the drug substance;
3. Therapeutic considerations, including consideration of the clinical indication to be treated and patient factor.

Table 1.1.: Dosage forms available for different administration routes

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The oral route of drug delivery is typically considered the preferred and most patient-convenient means of drug administration. In order to achieve prolong and effective action by oral route, sustained release dosage formulations are commonly used for maintaining therapeutic action of a drug for a specific time period. This type of dosage form can be defined as “the drug delivery system that is designed to release a drug at a predetermined rate by maintaining a constant plasma drug level for a specific period of time with minimum side effect by continuously releasing the active ingredient(s) after the administration of a single dose”.

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Figure 1.1: Pathways a drug may take following the administration of a dosage form by different route.

Most conventional dosage forms function merely to place a drug at the site of administration and pay no regard to the regulation of release and absorption or the duration and targeting of drug in the body. So, now-a-days one of the most active areas of research and development in drug delivery involves “controlled release” products rather than develop new drug entities at higher cost; as some drug therapies already on the market can be improved simply by controlling the rate at which they enter the blood stream as shown scheme-1

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Kr = rate constant for drug release, Ka = rate constant for drug absorption & Ke = rate constant for drug elimination.

Figure 1.2: Model for (a) Conventional Dosage form and (b) Sustained Release Dosage form Scheme -1 represents the model for conventional (a) & sustained release (b) oral drug movement in the body. The Kr & Ka values will be smaller for SR than conventional dosage form.

Oral sustained release dosage form by direct compression technique is a very modern and common approach in the pharmaceutical arena due to relatively ease, cost effective and faster production compared with other compression techniques. This technique also avoids hydrolytic or oxidative reaction occurred during processing of dosage forms.

After the administration of a dosage form, sustained or controlled drug delivery occurs while the active agent embedded with polymer(s) that may be natural or semi synthetic or synthetic in nature. The polymer is judiciously combined with a drug or other active ingredients in such a way that the active agent is released from the material in a redesigned fashion. The main target is that the active agent must be released at constant rate over a stipulated period of time. In most cases, the purpose of controlling or sustaining the drug delivery is to achieve more effective therapeutic action with eliminating the potential for both under and overdosing.

It is possible to formulate a sustain release dosage form in several techniques. But in the development studies of sustained release formulation, several new techniques, and approaches are also proving their acceptability and feasibility. Among the systems, matrix tablet has attracted much attention due its technological simplicity in comparison with other controlled release systems developed to achieve the sustained action.

In this study, direct compression method has been applied for preparation of tablet matrix that is most advanced technology ever discovered. It involves simple blending of all the ingredients along with the active agent used in the formulation and then underwent direct compression. It requires fewer unit operations, less machinery, reduced number of personnel and reduced processing time, increased product stability and faster production rate.

In general, the goal of a sustain release dosage form is to maintain therapeutic blood or tissue levels of the drug for an extended period. This is usually accomplished by attempting to obtain zero-order release from the dosage form. Zero-order release constitutes the drug release from the dosage form that is independent of the amount of drug in the delivery system (i.e. a constant release rate). This is usually achieved by incorporating one or more polymers with the active agent. But sustain release system generally do not attain this type of release and usually try to mimic zero-order release by providing drug in a slow first order fashion (i.e. concentration dependent).

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Figure 1.3: Drug level verses time profile showing differences between (a) traditional drug dosing and (b) sustained delivery dosing.

Depending on the route of administration, conventional dosage forms i.e. solution, suspension, capsule, tablet, cream, gel, ointment, suppository etc. produce effective drug concentration in blood vs. time for a short period of time. The short duration of action of the conventional dosage forms is due to their failure to control the delivery of the active agent. If any attempt is made to maintain drug blood level in the therapeutic range for longer periods increasing the dose, toxic effects of the drug may be produced at any time. An alternative is to administer the drug repetitively using a constant dosing interval as in multiple dosing therapies. In this case, effective drug blood level depends on both the dose and the dosing interval. There are some potential problems inherent to this multiple dose therapy. Primarily, if the dosing interval is not appropriate for the biological half-life of the drug, large peaks and valleys in the drug blood level may result within the therapeutic window. Secondly the blood level of the drug may not be reached within the therapeutic range at required time that is very important for certain disease states. Finally, the patient noncompliance with the multiple dosing regimens can result in the failure of the approach.

In recent years considerable attention has been focused on the development of new drug delivery systems. Recognition of the possibility of re-patenting success drugs by applying the concepts and techniques of controlled release drug delivery systems, coupled with the increasing expense in bringing new drug entities to market, has encouraged the development of new drug delivery systems. Therapeutic efficacy & safety of drugs administered by conventional methods can be improved by more precise, spatial, and temporal placement within the body, thereby reducing both the size and number of doses.

1.2. Historical viewpoints of controlled release drug delivery

The first sustained release dosage form was marketed in the United States in 1952 by Smith Kline & French under the trade name ‘Dexadrin Spansule’. The Spansule provided a novel form of drug delivery and was a major therapeutic breakthrough. It quickly released the required initial dose and then slowly and gradually released many extremely small doses to maintain a therapeutic level lasting from 10 to 12 hours, providing all-day or all-night therapy with one dose. The goal behind the development of oral controlled-release formulations at that time was the achievement of a constant release rate of the entrapped drug. On the basis of that concept, the zero-order osmotic delivery used in Procardia XL became one of the top 10 best-selling medicines in the past century (Das and Das, 2003).

In 1968, Alejandro Zaffaroni founded ALZA (ALZA Corporation, our Technologies, June 2004), now owned by Johnson and Johnson, with the aim of creating controlled drug delivery systems whose release rate of drug could be controlled with precision, independent of the release environment. The formation of ALZA marked the beginning of the modern era of drug delivery technology (Robinson, 1987). And Elan Corporation was founded in 1969 “with a vision: to approach the challenge of drug delivery from an entirely new angle - that of controlled absorption of a drug to provide longer duration of drug effect”.

Two major disease groups that have had an important bearing on the evolving nature of controlled drug delivery:

1. Diabetes - fluctuations in insulin/glucose minimized [sustained drug release]
2. Cancer - target abnormal cells [localized / targeted drug release]

From an economic point of view, the development of novel delivery systems can potentially prove profitable for a modest investment (in terms of acquiring market share). In Time magazine of Jan. 13th this year, Charles P. Wallace in 2003 wrote: "R and D costs as a percentage of drug-company sales were 12% in 1970, 15% in 1990, and 20% today". According to Visiongain, revenues of pharma products that utilize advanced drug delivery technology were estimated at US$38 billion in 2002. The growth of this market is expected to continue at an average rate of 28% over the next 5 years, significantly higher than the pace of the overall pharmaceutical industry (Corporate Fact Sheet, Q2 2005, www.mistralpharma.com).

Recently Controlled drug delivery industries have made certain standard innovation in drug delivery technology. Ms. Callanan commented, “Definitely a key for large pharma companies is to use novel approaches to extend the patent life of their products or, even if they don’t extend the patent life, to add something new to the compound to get marketing advantage. Things like fast-melt technology, extended release compounds, all those areas, those types of technologies; in the next few years they will be exploited to their fullest extent by large Pharmaceutical companies all over the world.”

Consider PROCISETM (www.mistralpharma.com/pdf/corporate_fact_sheetQ2_2005) is a programmable solid oral drug delivery system customized to the required release specification for a particular drug. The technology work on a unique patented tablet design and formulation. The PROCISETM system consists of a slow dissolving core with a cylindrical core in the middle. The surface of the core, excluding the peripheral edge, is covered with a very slow dissolving (slower than the active core) inert coating material. Dissolution of the core and drug release is therefore restricted to the peripheral edge. As the dissolution progresses over time, the core diameter decreases but the height of the cylindrical releasing surface increases thereby maintaining a constant surface area and thus constant release.

The popularity and importance of these dosage forms can be appreciated from the fact that for the first time in 1985 the official compendia adopted the use of the term “Modified Release” to identify these dosage forms as being different from the conventional dosage forms (USP XXI). The USP defines modified release dosage forms as “One for which the drug – release characteristics of time – course and /or location are chosen to accomplish therapeutic convenience not offered by conventional dosage forms.”

The majority of oral drug delivery systems are matrix-based. In such systems, the tablet is in the form of a compressed compact that contains an active ingredient, a lubricant, an excipient and a filler or binder. Erosion, diffusion, and swelling of the matrix are the various methods through which the systems control drug delivery. The polymer properties invariably play an important role in the release pattern of the drug. If the polymer is predominantly hydrophilic, the swelling process chiefly controls the drug release. The swellable matrices are monolithic systems prepared by compressing a powdered mixture of a hydrophilic polymer and drug. The success of these drug delivery systems is attributed to the established tablet manufacturing technology (Hogan, 1989). Thus hydrophilic matrices are an interesting option when developing an oral sustained-release formulation. They can be used for controlled release of both water-soluble and water-insoluble drugs. Release of drugs from such matrices can be controlled through their physical properties, the correct choice of gelling agent and setting up the conditions for fabrication (Vezquez et al., 1992).

The development of controlled release formulation continues to be a big success for the pharmaceutical industry. The success of any technology relies on the ease of its manufacturing process and its reproducibility of desirable biopharmaceutical properties. The market for oral controlled drug delivery alone is expected to grow at 9% or more every year through 2007 (Das and Das, 2003). The future of controlled – release products are promising especially in the areas of Chronopharmacokinetic systems and Mucoadhesive delivery (Amidon et al., 2000).

1.3. Sustained release drug delivery system

Sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. If the system is successful at maintaining constant drug levels in the blood or target tissue, it is considered as a controlled-release system. If it is unsuccessful at this, but nevertheless the duration of action over that achieved by conventional delivery, it is considered a prolonged-release system.

1.3.1. Concept of sustained release drug delivery system

Most conventional drug products, such as tablets and capsules, are formulated to release the active drug immediately to obtain rapid and complete systematic absorption of the drug. In recent years, various modified drug products have been developed to release drug products are designed for different routes of administration based on the physicochemical, pharmacological, and pharmacokinetic properties of the drug. Sustained release, sustained action, prolonged action, controlled release, extended action, time release, depot, and respiratory dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. In the case of injectable dosage forms; this period may vary from days to months. In the case of orally administered forms, however, this period is measured in hours and critically depends on the residence time of the dosage form in the GI tract (Ballard, 1978).

A more finite explanation of these types of medication has been provided by Nelson (1961) and Parrot (1963). They indicated that a sustained release or sustained action product provides an initial sufficient amount drug to cause a rapid onset of desired therapeutic response, and an additional amount of drug that maintains the response at the initial level for a desired number of hours beyond the activity resulting from conventional dose; the initial desired therapeutic response is maintained because the rate of release of the desired therapeutic concentration is equal to the rate at which the drug is eliminated or inactivated.

1.3.2. Rationale of sustained release drug delivery system

Depending on the route of administration, a conventional dosage form of the drug, e.g., a solution, suspension, capsule, tablet, etc., produce a drug blood level versus time profile which does not maintain within the therapeutic range for extended periods of time. The short duration of action is due to the inability of conventional dosage forms to control temporal delivery. If any attempt is made to maintain drug blood levels in the therapeutic range for longer periods, for example, by increasing the dose of an intravenous injection, toxic levels may be produced at early times. This obviously is undesirable and the approach therefore is unsuitable. An alternative approach is to administer the drug repetitively using a constant dosing interval as in multiple-dose therapy. In this case the drug blood level reached and the time required to reach that level depend on the dose and the dosing interval. There are several potential problems inherent in multiple-dose therapy. Firstly, if the dosing interval is not appropriate for the biological half-life of the drug, large `peaks’, and `valleys' in the drug blood level may result. For example, drug with short half-life may require frequent dosing to maintain constant therapeutic levels. Secondly, the drug blood level may not be within the therapeutic range at sufficiently early times, an important consideration for certain disease states. Thirdly, patient noncompliance with the multiple dose regimens can result in failure of this approach.

In general, controlled delivery attempts to:

1. Sustain drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with a saw-tooth kinetic pattern,
2. Localize drug action by spatial placement of a controlled release system (usually rate-controlled) adjacent to or in the diseased tissue or organ,
3. Target drug action by using carriers or chemical derivatization to deliver drug to a particular "target" cell type.

Sustained release dosage forms include those dosage forms in which the drug-release characteristics are different from the conventional dosage form to saw-tooth pattern of drug delivery (Except continuous IV perfusion) & results in increase adverse effects, decrease therapeutic effect & poor patient compliance (Madan, 1985)

In recent years considerable attention has been focused on the development of new drug delivery systems by applying the concepts and techniques of controlled release drug delivery. An appropriately designed sustained release drug delivery system can be a major advance toward solving the problems facing continuously in case of conventional dosage form, thereby reducing both the size and number of doses. It is for this reason that the science and technology responsible for the development of sustained release pharmaceuticals have been and continue to be the focus of a great deal of attention in both industrial and academic laboratories. The first such dosage form was marketed in the United States in 1952 by Smith Kline & French under the trade name Dexadrin spanules. At present more than 50 major manufactures produce about 200 special delivery products, representing nearly five percent of the pharmaceutical market (Madan, 1990).

1.3.3. Oral sustained release drug delivery system

The goal of sustained release drug delivery system is to supply the optimal concentration of a drug for a longer time than conventional system allows. For example, in case of immediate release tablet dosage form, medicine is ingested at intervals of specified time. When a tablet is taken, systemic drug concentration raises rapidly and then falls. After the ingestion of second tablet, the concentration of the active agent in the bloodstream again raises and then again falls. In this way, the cycle continues. The problem with this scenario is that optimal concentration cannot be maintained within the therapeutic window and the peaks may cross the toxic level. Also, human error may cause additional difficulties if a dose is delayed or missed. Sustained release systems directly combat these problems associated with the "Hill and Valley" phenomenon described above.

Oral sustained release drug delivery is a drug delivery system given by oral route that provides the continuous delivery of drug(s) to the systemic circulation at predictable and reproducible kinetics for a predetermined time period throughout the course of GI transit.

In the exploration of oral sustained release drug administration three potential changes are encountered. These are:

- Development of drug delivery system
- Modulation of gastrointestinal transit time
- Minimization of hepatic first pass elimination

In vitro drug release data, drug release profiles should be generated by a well-designed, reproducible in vitro testing method, such as the dissolution test for solid dosage forms.

The key elements for in vitro release are:

- Reproducibility of the method
- Proper choice of medium
- Maintenance of perfect sink conditions
- Good control of solution hydrodynamics

Controlled release dosage form is also known as­-

- Sustained release dosage form
- Prolonged release dosage form
- Delayed release dosage form
- Timed-release dosage form
- Retarded release dosage form
- Extended action dosage form
- Depot dosage form
- Repeat action dosage form
- Repository dosage form

1.3.4. Advantages of sustained release dosage forms

- Sustained release dosage forms maintain the therapeutic and prophylactic effect for longer period of time than can be obtained by immediate release single medication.
- For patient compliance as they reduce the number and frequency of doses administered.
- They reduce the total amount of drug needed to obtain the desired therapeutic response, thus maximize availability with a minimum dose.
- They reduce the incidence and intensity of both local and systematic adverse effects in sensitive patients caused by excessively high peak blood levels of drugs that may result from the administration of conventional dosage forms, thus safety margin of high potency drug can be increased.
- They reduce the possibility of the patients defaulting from treatment by forgetting to take his/her medication.
- They eliminate the inconvenience of night-time administration of drug.
- They reduce the necessity of nursing-staff in hospitals.
- Better control of drug absorption can be attained by sustained dosage forms.
- They reduce or eliminate “peak” and “valley” effects and thus maintain an even blood level of drug concentration in the body.
- In case of conventional dosage form of antibiotic during valley effect, the microorganisms may grow resistance against drug. But in case of sustained release dosage forms there is no chance of this, because they do not create peak and valley effect.

1.3.5. Disadvantages of sustained release dosage forms

- Sustained release dosage forms do not permit prompt termination of therapy when this is not desired or required.
- The physician has less flexibility in adjusting dosage regimens.
- They are comparatively more expensive than medication in conventional dosage form design.
- They are prepared on the basis of average rate of release and elimination. So, there may be drug accumulation.
- The sustained release dosage form contains the equivalent of two or more conventional dosage forms. Therefore, the failure of the sustained release dosage form might lead to dose dumping. Dose dumping may be defined as the release of more than the usual fraction of drug, or as the release of drug at a greater rate than the customary amount of drug per dosage interval, such that potentially adverse plasma levels may be reached.
- They produce a high concentration of drug at some specific sites along the GIT. This may cause local irritation to the GI mucosa.
- Effective drug release period is influenced by GI residence time.

1.3.6. Drugs unsuitable for sustained release dosage forms

- Drugs whose precision of dosage id important; e.g. Anticoagulants and Cardiac glycosides.
- Drugs having long biological half-life (>12 hrs); e.g. Diazepam, Phenytoin.
- Drugs whose absorption from the gastrointestinal tract is impaired or erratic; e.g. Riboflavin, Ferrous salts.
- Drugs having short biological half-life (<1hr); e.g. Penicillin G, Furosemide.
- Drugs whose large doses are required; e.g. Sulfonamides.
- Drugs with low therapeutic indices; e.g. Phenobarbital, Digitoxin.
- Drugs having no clear advantages for sustained release formulation e.g. Griseofulvin.

1.3.7. Factors affecting sustained release dosage forms:

Table 1.2: Factors affecting sustained release dosage forms

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1.3.7.1 Physicochemical properties of the drug affecting sustained release dosage forms:

a) Dose size:

If an oral product has a dose size greater than 0.5gm it is a poor candidate for sustained release system, Since addition of sustaining dose and possibly the sustaining mechanism will, in most cases generates a substantial volume product that unacceptably large.

b) Aqueous solubility of the drug:

Most of drugs are weak acids or bases, since the unchanged form of a drug preferentially permeates across lipid membranes drugs aqueous solubility will generally be decreased by conversion to an unchanged form for drugs with low water solubility will be difficult to incorporate into sustained release mechanism. The lower limit on solubility for such product has been reported 0.1mg/ml. drugs with great water solubility are equally difficult to incorporate in to sustained release system. pH dependent solubility, particularly in the physiological pH range, would be another problem because of the variation in pH throughout the GI tract and hence variation in dissolution rate

c) Stability of the drug:

Orally administered drugs can be subject to both acid base hydrolysis and enzymatic degradation. Degradation will proceed at the reduced rate for drugs in the solid state, for drugs that are unstable in stomach; systems that prolong delivery ever the entire course of transit in GI tract are beneficial. Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered form a sustaining dosage from. This is because more drug is delivered in small intestine and hence subject to degradation.

d) Partition coefficient of the drug:

Partition coefficient is generally defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase. Accordingly compounds with relatively high partition coefficient are predominantly lipid soluble and consequently have very law aqueous solubility. Compounds with very law partition coefficients will have difficulty in penetrating membranes resulting poor bioavailability.

d) pKa value of the drug :

The relationship between pKa of compound and absorptive environment. Presenting drug in an unchanged form is adventitious for drug permeation but solubility decrease as the drug is in unchanged form.

e) Protein binding:

It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Since blood proteins are for the most part re-circulated and not eliminated, drug Protein binding can serve as a depot for drug producing a prolonged release profile, especially if a high degree of drug binding occurs.

Extensive binding to plasma proteins will be evidenced by a long half-life of elimination for drugs and such drugs generally most require a sustained release dosage form. However drugs that exhibit high degree of binding to plasma proteins also might bind to bio-polymers in GI tract which could have influence on sustained drug delivery.The presence of hydrophobic moiety on drug molecule also increases the binding potential.

f) Molecular size and diffusivity:

The ability of drug to diffuse through membranes it’s so called diffusivity & diffusion coefficient is function of molecular size (or molecular weight).

Generally, values of diffusion coefficient for intermediate molecular weight drugs, through flexible polymer range from 10-8 to 10-9 cm2/sec. with values on the order of 10-8 being most common for drugs with molecular weight greater than 500, the diffusion coefficientin many polymers frequently are so small that they are difficult to quantify i.e. less than 16-12 cm2/sec.Thus high molecular weight drugs and/or polymeric drugs should be expected to display very slow release kinetics in sustained release device using diffusion through polymer membrane.

g) Protein binding:

It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Since blood proteins are for the most part re-circulated and not eliminated, drug Protein binding can serve as a depot for drug producing a prolonged release profile, especially if a high degree of drug binding occurs.

Extensive binding to plasma proteins will be evidenced by a long half-life of elimination for drugs and such drugs generally most require a sustained release dosage form. However drugs that exhibit high degree of binding to plasma proteins also might bind to bio-polymers in GI tract which could have influence on sustained drug delivery.The presence of hydrophobic moiety on drug molecule also increases the binding potential.

1.3.7.2. Biological properties of the drug affecting sustained release dosage forms:

a) Biological half-life of the drug:

The usual goal of an oral sustained release product is to maintain therapeutic blood levels over an extended period. To action this, drug must enter in the circulation of approximately the same rate of which it is eliminated. The elimination rate is quantitatively described by half-life (t1/2). Therapeutic compounds with short half-lives are excellent candidates for sustained release preparations. Since this can reduce dosing frequency. In general drugs with half-lives shorter than 3hrs are poor candidates of sustained release dosage forms of dose size will increase as well as compounds with long half-lives, more than 8 hrs. are also not used in sustained release forms because their effect is already sustained.

b) Absorption characteristics of the drug:

The rate, extent, and uniformity of absorption of a drug are important factors when considered its formulation into a sustained release system. As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than absorption. Rapid rate of absorption of drug, relative to its release is essential if the system is to be successful. It we assume that transit time of drugmust in the absorptive areas of the GI tract is about 8-12 hrs. The maximum half-life for absorption should be approximately 3-4 hrs. Otherwise device will pass out of potential absorption regions before drug release is complete.

c) Distribution characteristics of the drug:

The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. Since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently apparent volume of distribution assumes different values depending on time course of drug disposition. For design of sustained/ controlled release products, one must have information of disposition of drug.

d) Metabolism characteristics of the drug:

Drugs that are significantly metabolized before absorption, either in lumen or the tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzymes systems are saturable. As drug is released at a slower rate to these regions less total drug is presented to the enzymatic. Process device a specific period, allowing more complete conversion of the drug to its metabolite.6

e) Duration of action of the drug:

The biological half-life and hence the duration of action of a drug obviously plays a major role in considering a drug for sustained-release systems. Drugs with short half-lives and high doses impose a constraint because of the dose size needed and those with long half-lives are inherently sustained.

f) Margin of safety of the drug:

Drug with a narrow therapeutic range require precise control over the blood levels of drug, placing a constraint on sustained-release dosage forms.

1.3.8. Formulation methods used to prepare sustained release dosage form:

It includes:

- Particle size modification
- Matrix system
- Coating system
- Beads & spheres
- Enteric-coated beads in capsule
- Repeat action tablet
- Mix release granules
- Erosion core with initial dose
- Erosion core only
- Ion exchange resin
- Complexion
- Micro encapsulation
- The osmotic tablet
- Gel forming hydrocolloids
- Environmentally responsive system

1.3.8.1. Particle size modification

The solubilization of a drug is directly related to the surface exposed to the solvent. The purpose of increasing particle size is to decrease the surface area of the particle thus to decrease the release of the drug from the dosage form.

1.3.8.2. Matrix system

The matrix system is defined as uniform dispersion of drug in a solid which is less soluble than the drug in the depot fluid and which is the continuous internal phase of dispersion, effectively inhibits the passage of drug from the matrix to the depot fluid. Release is controlled by a combination of several physical factors, which include permeation of the matrix, by water, leaching and erosion of matrix materials, number of porous channels etc. It is one of the of the less complicated approaches in the manufacture of sustained release dosage forms which consists of a drug dispersed in a polymer the polymer plays the role of a matrix.

Several workers have also reported that the rate of drug release from the matrix system is affected by-

- Drug solubility
- The compression force applied
- pH of the dissolution fluid
- Shape
- External agitation
- Mass of the drug
- Porosity of the matrix

1.3.8.3. Coating system

Coating with a material that retards penetration of the depot fluid may control the rate of availability of drug from the dosage form. Drug release rate depends upon the physicochemical nature of the coating material. The dosage form itself or the individual particles may be coated.

1.3.8.4. Beads & sphere

The beads and spheres of drug are coated with a material that differs in thickness from bead to bead, determining the time at which the drug will be released. Release is controlled by using waxes that erode with time, chemicals that dissolved at a particular pH or compound the release the drug by diffusion through their pores. A number of materials are reportedly useful for such coatings including mixtures of bees wax or carnauba wax with glyceryl monostearate, stearic acid, palmitic acid, glyceryl myristate, cholesterol, such higher fatty alcohols, & esters of fatty acids of high molecular weight.

1.3.8.5. Enteric coated beads in capsule

This strategy incorporated drug into beads or spheres of uniform size and uniformly coated with a suitable enteric coating material. Thus the rate of drug release depends on stomach emptying rate of the beads. Since there will be large number of beads, their stomach emptying rate will be randomized, the overall pattern approaching normal distribution to eliminate the "all or none" affect associated with enteric coated tablet, and capsules. The total release pattern approaches a constant value, providing sustained and continuous release of drug.

1.3.8.6. Mixed release granules

This method uses granules as use in the preparation of compressed tablet. Two sets of granules are used. One set, which carries the immediate-release component of the drag, is prepared in the usual manner. The second set contains drug that is either coated with slowly digestible or poorly soluble materials or mixed with dissolution retarding additives. Hydrogenated vegetable oils, a number of waxes, fatty acids, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, mixtures of some of these glyceryl esters and bees wax or higher fatty alcohol & higher fatty acids used either singly or as mixture, have all been used in the preparation of such granules.

1.3.8.7. Repeated action tablets

Repeated action tablet contains an individual dose which is released fairly soon after administration, and second or third doses are subsequently released at intermittent intervals.

1.3.8.8. Erosion core with initial dose

In this method the sustaining component is formulated as a non-disintegrating tablet that essentially maintains its geometric its ape throughout the gastrointestinal tract. The drug in this component is usually incorporated into a tablet with insoluble materials such as high-molecular weight fats & waxes.

The principle of sustained drug release from the non-disintegrating tablet is based on the fact that the dissolution, rate of the drug from such tablet is directly proportional to the product of the drug's solubility & the tablet surface area.

1.3.8.9. Erosion core only

Many drugs do not require an initial dose when the primary purpose is to maintain a therapeutic consideration once therapy has been initiated. In such cases it may be more appropriate to formulate the dosage form to contain only the sustained-release component.

1.3.8.10. Ion-exchange resin

The phenomenon of ion exchange presents a useful method of sustaining action control. Ion-exchange resins are water-insoluble cross linked polymers containing salt forming groups in repealing positions on the polymer chain. Drug molecules are attached to the anionic or cationic group of ion-exchange resin and due to attachment drugs release is regarded.

The ion-exchange method involves the administration of a dosage form containing salts of drugs complexes with an ion-exchange resin that exchanges the drug for ions as it passes through the gastrointestinal tract.

1.3.8.11. Complexation

The preparation of complexes or salts of active drugs that are slightly soluble in the gastrointestinal fluid is the strategy used in this method of producing sustained-release product.

1.3.8.12. Microencapsulation

Microencapsulation is a means of relatively thin coating to small particles of solids or droplets of liquids and dispersion. Drugs from many pharmacological classes have been micro encapsulated in particular analgesic, antibiotics, antihistamines, cardiovascular agents, iron salts, tranquilizers, and vitamins. There are many reports in the literature regarding the reasons of micro encapsulation of drugs and related chemicals.

1.3.8.13. The osmotic tablet

The oral osmotic tablet is also a relatively recent addition to sustained-release tablet technology. This device consists of a core tablet & a semi permeable coating with a hole, produced by a laser beam, through which the drug exists. The product operates on the principle of osmotic pressure, which develops us gastrointestinal fluids permeate the semi permeable membrane & reach the core. These fluids dissolve the drug contained in the core & the osmotic pressure forces (or pumps) the drug solution out of the delivery orifice.

1.3.8.14. Gel forming hydrocolloids

Roche's recent produce 'Valueless' is based on this new technology. Capsules are filled with a dry mixture of drug & hydrocolloids. Upon dissolution of the capsule shell, the gastric fluids swell. The outermost hydrocolloid forms a gelatinous mass which acts as a barrier, preventing further penetration of gastric fluids. Initially, only the outer portion forms a gel & the center remains dry. The gelatinous erodes, exposing the next inner portion of hydrocolloid to the gastric fluid, with subsequent formation of a new barrier layer. The process continuously releases the drug as each gelatinous layer continues to erode & a new layer forms. The gelatinous mass formed on contact with gastric fluid has a low density & therefore its gastric transit time is prolonged.

1.3.8.15. Environmentally responsive system

It is as also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment. Swelling-controlled release systems are initially dry and, when placed in the body will absorb water or other body fluids and swell. The swelling increases the aqueous solvent content within the foundation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. Examples of these types of devices are shown in Figures 1.3 and 1.4 for reservoir and matrix systems, respectively. Most of the materials used in swelling-controlled release systems are based on hydrogels, which are polymers that will swell without dissolving when placed in water or other biological fluids. These hydrogels can absorb a great deal of fluid and at equilibrium, typically comprise 60-90% fluid and only 10-30% polymer.

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Figure 1.4: Drug deliveries from (a) reservoir and (b) matrix swelling-controlled release system

One of the most remarkable, and useful, features of a polymer's swelling ability manifests itself when that swelling can be triggered by a change in the environment surrounding the delivery system. Upon the polymer, the environmental change can involve pH, temperature, or ionic strength, and the system can either shrink or swell upon a change in any of these environmental factors. A number of these environmentally sensitive or "intelligent" hydrogel materials are listed in Table 1.2. For most of these polymers, the structural changes are reversible and repeatable upon additional changes in the external environment. The diagrams in Figure 1.4 illustrate the basic changes in structure of these sensitive systems. Once again, for this type of system, the drug release is accomplished only when the polymer swells. Because many of the potentially most useful pH-sensitive polymers swell at high pH values and collapse at low pH values, the triggered drug delivery occurs upon an increase in the pH of the environment. Such materials are idea for systems such as oral delivery, in which the drug is not released at low pH values in the stomach but rather at high pH values in the upper small intestine.

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Figure 1.5: Drug delivery from environmentally sensitive release system

1.3.9. Methods and mechanisms of sustaining drug action:

- Diffusional systems
- Reservoir devices
- Matrix devices
- Dissolution controlled systems
- Encapsulation
- Matrix
- Water penetration controlled systems
- Osmotically controlled
- Swelling controlled
- Chemically controlled systems
- Bioerodible systems
- Drug covalently linked with polymer
- Hydrogels
- Chemically controlled
- Swelling controlled
- Diffusion controlled
- Environment responsive
- Ion-exchange resins
- Cationic exchange
- Anionic exchange

1.3.9.1. Diffusional systems

Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert water insoluble membrane barrier.

There are basically two types of diffusion devices.

(I) Reservoir devices
(II) Matrix devices

- Reservoir Devices:

Reservoir devices are those in which a core of drug is surrounded by polymeric membrane. The nature of membrane determines the rate of release of drug from the system.

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Figure 1.6: Polymeric membrane controls the release of drug from the device

The process of diffusion is generally described by a series of equations governed by Fick’s first law of diffusion.

J = - D (dc/dx) --------------------------(1)

Where,

J= Flux of drug across the membrane given in unit of amount / area-time

D = Diffusion coefficient of drug in membrane in units of area / time. This is a reflection of the drug molecule’s ability to diffuse through the solvent and is dependent on molecular size and charge.

dc/dx = Rate of change in concentration c relative to a distance x in themembrane.

The law states that amount of drug passing across a unit area, is proportional to the concentration difference across that plane.

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