Chapter 1 Introduction

Transcription

1 Chapter 1 SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai

2 1.0 Extended release dosage form In the past few decades, significant advances have been made in the area of drug delivery with the development of novel dosage forms. The area of extended drug delivery has graduated from being merely a research item to result in full-fledged commercial reality products. An appropriately designed extended release drug delivery system can be a major advance towards solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target sites. On the other hand, there is a growing need for the controlled and or continuous delivery of such therapeutic agents due to several biopharmaceutical, safety and patient compliance issues associated with these therapies. Extended release systems provide drug release in an amount sufficient to maintain the therapeutic drug level over an extended period of time, with the release profiles predominantly controlled by the special technological construction and design of the system itself. Development of oral extended release systems has been a challenge to formulation scientists due to their inability to restrain and localize the system at targeted areas of the gastrointestinal tract. There are numerous products in the market formulated for both oral and parenteral routes of administration that claim extended or controlled drug delivery. Matrix type drug delivery systems are one of the interesting and promising options in developing an oral extended release system. In particular, the interest awakened by matrix type delivery is completely justified in view of its biopharmaceutical and pharmacokinetic advantages over the conventional dosage forms 1. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly, and then maintain the desired drug concentration. This idealized objective of delivering drug at a rate dictated by the needs of the body over the period of treatment, points to the two aspects most important to drug delivery, namely, spatial placement and temporal delivery of a drug. Spatial placement relates to targeting a drug delivery to the target tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue. Despite significant interest and numerous reports about the design of extended delivery systems for various types of drugs, very few have been successful 2. For non-immediate release dosage forms, Kr <<<< Ka, that is release of drug from the dosage form is the rate limiting step and not absorption as is the case with immediate release dosage forms. Therefore the kinetic scheme is reduced as: SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 2

3 Dosage form Drug (*) Release Target area Elimination (*) indicate rate limiting step Fig.1.1: Kinetic scheme of release and elimination of the drug from non- immediate release dosage forms. Essentially the absorptive phase of the kinetic scheme becomes insignificant compared to the drug release phase. Thus, the effort to develop a modified release delivery system must be directed primarily at altering the release rate by affecting the value of Kr. 1.1 Comparison of immediate release dosage form with extended release dosage form Over the past decades the treatment of acute and chronic illness has been accomplished by many conventional drug delivery systems such as tablets, capsules, pills, creams, ointments, liquids, aerosols, injectables and suppositories. These conventional drug delivery systems are still the primary pharmaceutical products commonly seen today in prescription. Oral route is the most commonly employed route of drug administration. Although different routes of drug administration are used for the delivery of drugs, oral route remains the preferred route. Even for extended release systems the oral route of administration has been investigated the most, because of flexibility in dosage form design that the oral route offers 3. Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability. For most drugs, conventional method of drug administration is effective, but some drugs are unstable or toxic and have narrow therapeutic ranges 3-5. In these types of systems, frequent dosing is required for achieving and maintaining concentration of drug within the therapeutic range, which result into see-saw pattern of the drug levels, in such cases, a method of continuous administration of therapeutic agent is desirable to maintain fixed plasma level as shown in figure 1.2. To overcome these problems extended release systems were introduced three decades ago. Extended release, extended action, prolonged release, controlled release, extended action, timed release, depot and redepository dosage forms are the 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 single dose. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 3

4 Term controlled release has become associated with those systems from which therapeutic agents may be automatically delivered at predefined rate over long period of time. Figure 1.2: Drug blood level versus time profile showing the relationship between conventional release and controlled delivery system The basic goal of drug therapy is to achieve a steady-state blood level or tissue level that will be therapeutically effective and non-toxic for an extended period of time 4. To achieve better therapeutic action various types of drug delivery systems are available, out of which extended release systems are gaining much importance because of their wide advantages over other like ease of administration, convenience and non-invasiveness. The vast majority of traditional dosage forms can be described as dump systems which deliver their active substances in first order kinetics i.e., release occurs at rates that are highest initially and then decline steadily thereafter. Clinically this peak and valley pattern results in a time dependant mix therapy. Drug side effects tend to predominate at the high peak concentration in blood, whereas an inadequate therapeutic effect may prevail at the valley level. Use of controlled release systems provide an excellent tool to achieve precise control of rate (and also) at a particular site. Besides, from the biological benefits incurred from the prolonged and predictable drug levels extended release systems can allow for significant reduction in frequency of drug administration and improved patient compliance, more predominantly for chronic ailments such as high blood pressure, arthritis, asthma and diabetes. There are also good commercial reasons for strong trend towards extended release system. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 4

5 3, 6, Terminology Different terminologies used for extended drug delivery system are as follows Modified Release (MR): Modified Release dosage forms are defined by USP as those whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional forms, whereas an extended release dosage form allows a two-fold reduction in dosing frequency or increase in patient compliance or therapeutic performance. Sustained Release (SR): It indicates an initial release of the drug sufficient to provide a therapeutic dose soon after administration, and then a gradual release over an extended period. Extended Release (ER): Extended release dosage forms release drug slowly, so that plasma concentration are maintained at therapeutic level for prolonged period of time. Clear or well defined distinction cannot be made in the above terminology. Sometimes it is conveniently referred in a particular place or group. 1.2 Fundamental release theories Based on different drug release mechanisms, quite a few drug release theories have been developed. For all different types of controlled release systems except osmosis based systems, the drug concentration difference between formulation and dissolution medium plays a very important role in drug release rate. The drug concentration can be affected by its solubility, drug loading, and / or excipients used. Besides drug concentration difference, the dissolution rate of polymer carriers can affect drug release rate in dissolution controlled systems, and the diffusion rate of both drug and dissolution medium inside polymer(s) can affect drug release rate in diffusion controlled systems. Overall, for most CR formulations, drug release can be affected by more than one mechanism. Fick s first law of diffusion is used, in which the concentration with the diffusion volume does not change with time. The drug release rate is determined by drug release surface area (s) thickness (h) of transport barrier (such as polymer membrane or stagnant water layer) and the concentration difference ( C) between drug donor (C d ) and receptor (C r ) that is, between drug dosage surface and bulk medium. C d C h C r Figure 1.3 Fick s Law SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 5

6 Fick s first law states that J = dm S.dt Where J is flux, M is the total amount of solute crossing surface area S in time t. Fick s first law did not take into account the drug concentration changes with time in each diffusion volume, which have been taken into consideration by Fick s second law of diffusion. Based on Fick s second law, drug accumulation speed (dc/dt) is determined by drug diffusivity (D) and the curvature of drug concentration dc dt = D d 2 C dx 2 Most commonly seen drug release rate for oral controlled release formulation is first order release and / or zero order release. Most oral controlled release formulations based on matrix and coating approaches are close to first order release. There are mainly five types of release profiles, zero order release (constant release rate), first order release (decreasing release rate), bimodal release (two release modes rate) which can be either two separate immediate release modes or one immediate release mode followed by one extended release mode 8-10, pulsatile release (multiple release modes and multiple peaks of release rate 11 and delayed release (e.g. enteric coated tablets) The two important phenomena in controlled release formulations are the lag time effect and the burst effect. In diffusion control system, if fresh membrane is used, it takes time for drug molecules on the donor side to appear on the receptor side. Under sink condition, drug molecules will be released at constant rate into the receptor side and steady state is reached. The time to reach steady state is known as lag time however, if the membrane saturated with drug is used, a burst effect will be observed at the beginning of drug release, gradually, the drug concentration inside the polymer membrane will decrease until the steady state is reached. Actually, for matrix approach controlled release formulation, because it takes time for polymer molecules to form Hydrogel, burst effect is also a common phenomenon Limiting factors for oral extended release formulations There are a few unique properties of the gastrointestinal (GI) tract that make development of oral ER formulation rather difficult. Figure 1.1 shows schematic description of GI tract. Based on histology and function, small intestine is divided into duodenum, jejunum, and ileum, and large intestine is divided into the cecum, colon, rectum, and anal canal. W. A. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 6

7 Ritschel reported the average length, diameter, and absorbing surface area of different segments of the GI tract, and the data clearly show that jejunum and ileum (small intestine) have similar surface absorbing area that are significantly larger than those of other segments 15. For most drugs, there is better drug absorption in the upper GI tract, which is also consistent with the significant higher surface absorbing area in the upper GI tract. Table 1.1: ph values and the transit time at different segments of the human GI tract16 20 Parts of intestine- Anatomical site Fasting condition ph Transit Time (h) Fed condition ph Transit Time (h) Stomach Duodenum Jejunum Ileum Cecum Colon Relatively short gastric empty and intestinal transit time and varying ph values As oral dosage forms will be removed from the GI tract after a day or so, most oral ER formulations are designed to release all drugs within hrs. The values in table 1.1 show the approximate transit time in different GI segments. The presence of food in the stomach tends to delay gastric emptying. Among different foods, carbohydrates and proteins tend to be emptied from stomach in less than 1h, while lipids can stay in the stomach for more than 1h As a convenient resource, Gastroplus TM can provide rough estimation on the transit times and ph values of the GI tract under different situations and help to determine corresponding drug PK profiles. Table 1.1 shows that the small intestinal transit time is more reproducible and is typically about 3 4 hrs. Thus, transit time from mouth to cecum (the first part of large intestine) range from 3-7 hrs. Colonic transit is highly variable and is typically hrs Since most drugs are absorbed from small intestine, the time interval from mouth to cecum for oral controlled release dosage forms is too short, unless the drug can be equally absorbed from large intestine, thus the release profiles of most oral controlled release dosage forms can be effective for only about 8 hrs., if the drug can be delivered for 24 hrs. with a single administration of an oral controlled release dosage form. But many drugs require more than one administration if they have the upper GI tract absorption window and short half life, unless the release of those drugs can be controlled at the upper GI tract with special design. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 7

8 The study on the GI transit time of once a day OROS tablets of both oxprenolol and 24, 25 metoprolol showed that the median total transit time was 27.4 hrs. with a range of Nonuniform absorption abilities of different segments of GI tract drug transport across the intestinal epithelium in each segment are not uniform, and in general, it tends to decrease as the drug moves along the GI tract. Drug absorption from different regions of the GI tract is different; the residence time of drug within each segment of that GI tract can profoundly affect the performance of the oral controlled dosage form, that is, the absorption of drug. If a drug is absorbed only from the upper segment of the GI tract, it is known to have a window for absorption 26. For the drugs with window for absorption; adjusting drug release rate on different segments of the GI tract may be needed to compensate decreased absorption, in order to maintain relatively constant blood concentration. For example, to achieve a plateau shaped profile to plasma concentration at steady state throughout the 24 hrs. dosing interval, Nisoldipine coat core controlled release formulation releases drug slowly in the upper GI tract that has fast absorption and quickly in the colon that has decreased absorption rate 28. Besides adjusting drug release rate, increasing the residence of drug formulations at or above the absorption window can also enhance the absorption for those drugs. Currently, two main approaches have been explored; bioadhesive micro spheres that have a slow intestinal transit and the gastro retentive dosage system 27, Presystemic clearance for drugs Presystemic clearance may occur at some sites of the GI tract and affect drug absorption. Degradation of orally administered drugs can occur by hydrolysis in the stomach, enzymatic digestion in the gastric and small intestinal fluids, metabolism in the brush border of the gut wall, metabolism by microorganisms in the colon, and or metabolism in the liver prior to entering the systemic circulation (i.e. first pass effect). Such degradation may lead to highly variable or poor drug absorption into the systemic circulation. For example, digoxin undergoes microbial metabolism before absorption 29, 30. For this type of drugs, for which presystemic clearance is determined by the site of absorption, drug bioavailability can be enhanced by restricting drug delivery to the upper segment of the gut, or to the stomach. For example, the same amount of metoprolol was administered at the same rate using a continuous 13.5 h intragastric infusion or an OROS tablet at 6-15 hrs. After dosing, the intra gastric infusion had higher plasma concentration than OROS tablet 31, 32. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 8

9 1.3 Criteria for selection of drug candidates for formulation of oral extended release dosage form 33 The design of extended release systems depends upon various factors such as the route of administration, the type of delivery system, the disease being treated and the properties of drug. These are either physicochemical or biological properties of the drugs Physicochemical properties Aqueous solubility Absorption of poorly soluble drugs is often dissolution rate limited. Such drugs do not require any further control over their dissolution rate and thus may not seem to be good candidates for extended release systems. Drugs with good aqueous solubility make good candidates for oral extended release formulation Partition coefficient Drugs that are very lipid soluble or very water soluble i.e., extremes in partition coefficient will demonstrate either low flux into the tissue or rapid flux followed by accumulation in tissue. Both cases are undesirable for extended release formulation Drug stability As most oral extended release systems are designed to release their content over much of the length of GI tract, drugs which are unstable in the environment of intestine are difficult to formulate into prolonged release systems. Interestingly, placement of such drugs in extended release system also improves the bioavailability picture Protein binding Protein binding characteristics of drug can play significant role in the therapeutic effect, regardless of type of dosage form. Extensive protein binding can be evident by long half life elimination for the drug, and such drugs do not require extended release dosage form. However, drugs that exhibit high degree of binding to plasma protein also might bind to biopolymer in the GI tract, which could have influence on extended drug delivery Molecular size and difficulty Drugs in many extended release systems must diffuse through a rate controlling membrane or matrix, in addition to diffusion through various biological membranes. The ability of drug to pass through membrane is called as diffusivity. It is function of its molecular weight. An important influence upon the value of diffusivity (D) in polymers is the molecular size of SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 9

10 diffusing species. The value of diffusivity is related to the size and shape of cavities as well as the size and shape of diffusing species Biological half-life The usual goal of extended release product is to maintain therapeutic blood level over an extended period of time. For this, rate at which the drug enters the circulation must be approximately equivalent to the rate of its elimination which is quantitatively described by its half-life. Drugs with shorter half-life 2-4 hrs make excellent candidates for extended release preparation since this can reduce dosing frequency. Drugs with half-life shorter than 2 hrs will require excessive amount of drug in each dosage form to maintain extended effect i.e., if the dose of drug is high. 1.4 Biological properties Absorption To maintain a constant blood or tissue level of drug it must be uniformly released from the extended release system and then uniformly absorbed. Usually, the rate limiting step in drug delivery from extended release product is release from the dosage form, rather than inherent absorption control. The fraction of drug absorbed from a single non-sustained dose of drug can be quite low due to drug degradation, binding to proteins or dose dependent absorption. Even if the drug is uniformly absorbed but incompletely, a successful release product can be made. Dicoumarol and the amino glycosides, gentamicin and kanamycin are examples of drugs erratically absorbed after oral administration, making the design of extended release product e.g. riboflavin Distribution Distribution of drugs into tissues is a major factor in the overall drug elimination kinetics. Drugs with high apparent volume of distribution, which in turn influences the rate of elimination for the drugs, are poor candidates. It influences the concentration and amount of drug either in the blood or in the tissues. While designing extended release systems the apparent volume of distribution can be used to obtain information concerning drug dosing Metabolism Metabolism leads to either inactivation of an active drug moiety or activation of an inactive drug molecule. Metabolic alteration of a drug mostly occurs in the liver. Metabolism is reflected in the elimination constant of a drug or by the appearance of metabolite provided the rate and extent of metabolism are predictable. This property can be incorporated into the SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 10

11 product design, although complex metabolic patterns make design more difficult, particularly when biological activity is due to a metabolite. If the drug on administration induces or inhibits enzyme synthesis, it will make a poor candidate for extended release product because of the difficulty of maintaining uniform blood level Duration of action The biological half life and hence the duration of action of a drug is influenced by its distribution, metabolism and elimination patterns and plays a key role in determining the candidature of the drug for preparation as extended release product. Drugs with short halflives require frequent dosing to minimize the fluctuation in blood levels accompanying conventional oral dosage regimen and controlled release dosage form would appear highly desirable for such drugs. However, for drug with a very short half-life, the desired rate of release will be quite large which will in turn lead to a prohibitively large dose, unsuitable for incorporation into an extended release unit. Similarly, there is little justification to prepare extended release formulation for drugs with long biological half-lives. If there is no significant difference in effectiveness when a drug is given as single large dose per day or in several smaller doses throughout the day, the need for prolonged action dosage form is doubtful, e.g. phenylbutazone and phenothiazines. Drugs with biological half-life of about 4 hrs. make good candidates for extended release products Side effects Extended release formulation can minimize the incidence of side effects by controlling the plasma concentration of the drug, e.g., controlled release levodopa has lowered the incidence of side effects and increased patient tolerance to a large total daily dose. The technique of controlled release has been more popularly used to lower the incidence of gastro-intestinal side effects than that of systematic side effects. Thus, drugs that are prone to cause gastric irritation are better tolerated in extended release dosage form, i.e., ferrous sulphate and potassium chloride Margin of safety Margin of safety of drug is commonly indicated by its therapeutic index. Drug is considered to be relatively safe if its therapeutic index exceeds 10. Therapeutic Index: Median toxic dose Median effective dose SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 11

12 In designing extended release systems for drugs with relatively narrow therapeutic indices, it is essential that the drug release pattern is precise to maintain the plasma concentration within a safe and effective therapeutic range. 1.5 Development of extended release solid oral products A pharmaceutical dosage form development program generally includes preformulation studies, analytical method development and validation, design development, scale up, optimization of formulation, manufacturing process, and stability studies. Because of the complexity of solid dosage forms and the challenges in applying the principles of basic and applied sciences in the pharmaceutical industry, the strategies and approaches that have been and continue to be utilized in solid product development vary significantly from company to company, and even across project teams within the same organization. Generally, modified release solid oral product can be developed by different approaches like trial and error, semi empirical and rationale as given in table 1.2. Table 1.2: Comparison of approaches to solid product development Approach Characteristics Likely outcome Trial and error Trying out various experiment or hypotheses in different directions until a desired outcome is obtained with some degree of reliability Lack of a consistent approach Disconnect between data and underlying mechanism Can often be overwhelmed or mislead by data generated from uncontrolled experiments with compounding variables, thus exacerbating problems, and inhibiting innovation Inconsistent or non-robust product and process that can often lead to failures during development or post approval product recalls Considerable waste of time, and resources, resulting in poor development efficiency SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 12

13 Approach Characteristics Likely outcome Semi empirical Combining experience with analysis of abundant data (often retrospectively) to identify trends or build empirical or semi empirical relationships Using best guessed trial and error approach based on prior knowledge Results can be practically useful, but may not be reliable or could be misleading in certain cases, due to improper design and limitation of experiments and /or lack of comprehensive scrutiny of pooled data, and formulation / process variables involved. Lack of fundamental understanding of underlying Mechanism Lower development Efficiency due to time and extensive resources required. Rationale Applying proactively comprehensive knowledge and techniques of multiple scientific disciplines and experience to the understanding of the characteristics of raw materials, delivery system, process, and in vivo performance Integrating formulation / process design and development by applying systematic approach, and utilizing interdisciplinary scientific and engineering principles Using the best guessed approach appropriately by combining prior knowledge with theoretical analysis in experimental designs Enhanced understanding of how material properties, process variables, and product attributes relate to product performance, as well as the interplays between biological system, and the drug substance or dosage form Greater product and process understanding for consistent product quality, improved control, and risk management Increased efficiency, decreased cost and product rejects Streamlined post-approval changes, and enhanced opportunities for continual improvement Confirm to quality by design principle under cgmp of the twenty first century SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 13

14 1.6 Types of oral extended release systems These days many types of commercial extended release preparations are available, none works by single drug release mechanism. Most extended action products release drug by a combination of processes involving dissolution, permeation, and diffusion. The single most important factor is water permeation, without which none of the products generally can control the rate at which the drug dissolves. Once the drug is dissolved, the rate of drug diffusion may be further controlled to a desirable rate 34. Following are the major extended release systems for oral use. Matrix technology Table 1.3: Controlled drug release mechanisms and related formulation Mechanism Related formulation approach Encapsulated dissolution system Dissolution (Reservoir system) Matrix dissolution system Reservoir system 1. Nonporous membrane reservoir 2. Microporous membrane reservoir Monolithic device 1. Nonporous matrix Diffusion. a) Monolithic solution b) Monolithic dispersion 2. Micro porous Matrix a) Monolithic solution b) Monolithic dispersion Osmotic Ion exchange Monolithic matrix These systems are considered in two groups Those with drug particles dispersed in a soluble matrix, with drug becoming available as the matrix dissolves or swells and dissolves (hydrophilic matrices). Those with drug particles dispersed in an insoluble matrix, with drug becoming available as a solvent enters the matrix and dissolves the particles (lipid matrices and insoluble polymer matrices). SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 14

15 Advantages of matrix systems 35 Excipient are generally cheap and usually GRAS (generally regarded as safe) Certified. Capable of sustaining high drug load and high molecular weight compound. Reproducible release profile. Uses readily available pharmaceutical manufacturing equipment. Possible to obtain different types of release profile: zero order or first order. Since the drug is dispersed in the matrix system, accidental leakage of the total drug component is less likely to occur, although occasionally, cracking of the matrix material can cause unwanted release. Disadvantages of the matrix systems The remaining matrix must be removed after the drug is released. The drug release rates vary with the square root of time. Release rate continuously diminishes due to an increase in diffusion resistance and / or a decrease in effective area at the diffusion front. However, a substantial extended effect can be produced through the use of very slow release rate, which in many applications are indistinguishable from zero order Lipid matrix systems Wax matrices are a simple concept. They are easy to manufacture using standard methods that is direct compression, roller compaction or hot melt granulation. The matrix compacts are prepared form blends of powdered components. The active component is contained in hydrophobic matrix that remains intact during drug release. Release depends on an aqueous medium dissolving the channeling agent, which leaches out of the compact, so forming a porous matrix of tortuous capillaries. The active agent dissolves in aqueous medium and, by way of water filled capillaries, diffuses out of the matrix. Wax matrices are simple unsophisticated delivery systems with a good control of rate and extent of drug release Insoluble polymer matrix system An inert matrix is one in which drug is embedded in an inert polymer which is not soluble in gastrointestinal fluid. Drug release from inert matrices has been compared to the leaching from sponge. The release rate depends upon drug molecules in aqueous solution diffusing through a network of capillaries formed between compacted polymer particles. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 15

16 The matrices remain intact during gastrointestinal transit. There have also been concerns that impaction may occur in large intestine and that patient may be concerned to see the matrix ghost in stool. More recently there has been renewed interest in this type of matrix, and polymers such as ethylcellulose are finding favor. The release rate of drug from inert matrix can be modified by changing the porosity and tortuosity of matrix, i.e. its pore structure. The addition of core forming hydrophilic salts or solutes will have a major influence, as can be manipulation of processing variables. Compression force controls the porosity of matrix and will release the drug more slowly than less consolidated matrix. The presence of excipient is likely to influence drug release. It may be anticipated that water soluble excipient will enhance the wetting of matrix, or increase its porosity on dissolution. Insoluble excipient will tend to decrease the wetability of matrix and reduce the penetration of dissolving medium. An increase in drug loading tends to enhance release rate, but the relationship between the two is not clearly defined. One possible explanation may be a decrease in the porosity of the matrix. As may be expected, release rate can be related to drug solubility Hydrophilic colloid matrix systems These delivery systems are also called swellable soluble matrices. In general they comprise a compressed mixture of drug and water swellable hydrophilic polymer. The system is capable of swelling, followed by gel formation corrosion and dissolution in aqueous media. Their behavior is in contrast to a true hydrogel, which swell on hydration but does not dissolve. On contact with water the hydrophilic colloid components swell to form a hydrated matrix layer. This then controls further diffusion of water into the matrix. Diffusion of drug through the hydrated matrix layer controls its rate of release. The outer hydrated matrix layer will erode as it becomes more dilute; the rate of erosion depends on the nature of the colloid. Hydrophilic colloid gels can be regarded as a network of polymer fibrils that interlink in some way. There is also a continuous phase in the interstices between the fibrils through which the drug diffuses Mechanisms of drug release from matrix systems Now days many types of commercial extended release preparations are available. None work by a single drug release mechanism. The release of drug from controlled devices is via dissolution or diffusion or a combination of the two mechanisms. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 16

17 Diffusion controlled systems In diffusion controlled extended release system the transport by diffusion of dissolved drug in pores filled with gastric or intestinal juice or in a solid (normally polymer) phase is the release controlling process. Depending on the part of the release unit in which the drug diffusion takes place, diffusion controlled release system are divided into matrix system (also referred to as monolithic system) and reservoir system. The release unit can be a tablet or a nearly spherical particle of about 1mm in diameter (a granule or a millisphere). In both cases the release unit should stay more or less intact during the course of the release process. In matrix system diffusion occurs in pores located within the bulk of the release unit as shown in figure ) The liquid that surrounds the dosage form penetrates, release units and dissolves the drug. A concentration gradient of dissolved drug is thus established between the interior and the exterior of the release unit. 2) The dissolved drug will diffuse from the pores of the released unit or the surrounding membrane and thus be released A dissolution step is thus normally involved in the release process, but the diffusion step is the rate controlling step. Figure 1.4: Release mechanism of matrix system In a matrix system the drug is dispersed as solid particles within a porous matrix formed of water insoluble polymer, such as polyvinyl chloride figure 1.4. Initially, drug particles located at the surface of the release unit will be dissolved and the drug is released rapidly. Thereafter, drug particles at successively increasing distances from the surface of the release unit will be dissolved and released by diffusion in the pores to the exterior of the release unit. This process continues with the interface between the bathing solution and the solid drug moving towards the interior. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 17

18 Fig 1.5: Schematic illustration of the mechanism of drug release from diffusion based on the matrix tablet (time) If this system is to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be faster than the diffusion rate of dissolved drug leaving the matrix 36. Derivation of the mathematical model to describe this system involves the following assumption 37, 38, 39 (Based on Fig 1.5). 1) a pseudo steady state is maintained during drug release; 2) the diameter of the drug particles is less than the average distance of drug diffusion through the matrix; the diffusion coefficient of drug in the matrix remains constant (no change occurs in the characteristics of the polymer matrix) 3) the bathing solution provides sink condition at all times; 4) no interaction occurs between the drug and the matrix; 5) the total amount of drug present per unit volume in the matrix is substantially greater than the saturation solubility of the drug per unit volume in the matrix (excess solute is present) 6) only diffusion process occurs Depleted matrix zone Drug Solid drug Cs dn Ghost matrix x=0 x=n Figure 1.6: Schematic representation of a matrix release system The release behavior can be described by the following equation SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 18

19 d m / d n = C 0. d h - C s /2 (1) Where, d m - change in the amount of drug released per unit area d n - change in the thickness of the zone of matrix that has been depleted of drug C 0 - total amount of drug in a unit volume of matrix C s saturated concentration of drug within the matrix From diffusion theory d m = D m C s /h.dt (2) By combining equation (1) and (2); M = [ C s.d m (2 C 0 - C s ). T)] 1/2 (3) When the amount of drug is in excess of saturation concentration, (C 0 >>Cs) M = [ 2C s.d m C D. T] 1/2 (4) This indicates that the amount of drug released is a function of square root of time. Drug release form a porous monolithic matrix involves the simultaneous penetration of surrounding liquid, dissolution of drug and leaching out to the drug through tortuous interstitial channels and pores. The volume and length of the opening must be accounted for in the drug release from a porous or granular matrix M = [D S Ca P / T ( 2C 0 p. C a ). t] 1/2 (5) Where, P = porosity of the matrix T = tortuosity C a = solubility of the drug in the release medium D s = diffusion coefficient in the release medium Porosity is the fraction of matrix that exists as pores or channel into which the surrounding liquid can penetrate. It is the total porosity of the matrix after the drug has been extracted; it consist of initial porosity due to the presence of air or void space in the matrix before the leaching process begins as well as the porosity created by extracting the drug and the water soluble excipeints. P = P a + C 0 / p + C ex /p ex (6) Where, p is the drug density and C ex are the density and the concentration of watersoluble excipient respectively. In case where no water soluble excipient is used in the formulation and initial porosity is much smaller tan porosity created by drug extraction, total porosity becomes. P = C 0 /p (7) SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 19

20 Hence the release equation can be written as; M = [D s C a P/T (2C 0 p. C a ).t] 1/2 (8) M = [2 D S. C a. C 0. P/T. t] ½ (9) For purpose of data treatment, equation (5) can be reduced to M = k.t 1/2 Where, k is a constant, so that the amount of drug released versus the square root of time will be linear, if the release of drug form matrix is diffusion controlled. If this is the case, one may control release of drug from a homogeneous matrix 40, 41, 42 system by varying the following parameters Initial concentration of drug in the matrix Porosity Tourtuosity Polymer systems forming the matrix Solubility of drug Dissolution controlled systems A drug with slow dissolution rate will demonstrate sustaining properties, since the release of the drug will be limited by the rate of dissolution. In principle, it would seem possible to prepare extended release products by decreasing the dissolution rate of drug that is highly water-soluble. This can be achieved by preparing an appropriate salt or derivative coating the drug with a slowly dissolving material encapsulation with dissolution control incorporating the drug into a tablet with a slowly dissolving carrier- matrix dissolution control (a major disadvantages is that the drug release rate continuously decreases with time) The dissolution process can be considered diffusion layer controlled, where the rate of diffusion from the solid surface to the bulk solution through unstirred liquid films is the determining step. The dissolution process at steady state is described by Noyes -Whitney equation Dc /dt = k D.A (C S C) = D /h.a. (C S C) Where, D c /d t = dissolution rate K D = the dissolution rate constant (equivalent to the diffusion coefficient divided by the thickness of the diffusion layer D/h) SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 20

21 D = diffusion coefficient C S = saturation solubility of the solid C = concentration of solute in the bulk solution Equation (1) predicts that the rate of release can be constant only if the following parameters are held constant; Surface area Diffusion coefficient Diffusion layer thickness Concentration difference Erosion controlled system In erosion controlled extended release systems the rate of drug release is controlled by the erosion of matrix in which the drug is dispersed. The matrix is normally a tablet, i.e., the matrix is formed by tableting operation, and the system can thus be described as a continuous liberation of matrix material (both drug and excipient) from the surface of the tablet, i.e. surface erosion. The consequence will be a continuous reduction in tablet weight during course of the release process (figure 1.6). Drug release from an erosion system can thus be described in two steps 1) Matrix material, in which the drug is dissolved or dispersed, is liberated from the surface of the tablet. 2) The drug is subsequently exposed to the gastrointestinal fluids and mixed with (if the drug is dissolved in the matrix) or dissolved in (if the drug is suspended in the matrix) the fluid. This release scheme is in practice a simplification, as erosion systems may combine different mechanisms for drug release. For example, the drug may be released both by erosion and by diffusion within the matrix. Thus, a mathematical description of drug release from an erosion system is complex. However, drug release can often approximate zero-order for a significant part of the total release time. The eroding matrix can be formed from different substances. One example is lipids or waxes, in which the drug is dispersed. Another example is polymers that gel in contact with water (e.g. hydroxy ethyl cellulose). The gel will subsequently erode and release the drug dissolved or dispersed in the gel. Diffusion of the drug in the gel may occur in parallel as shown in figure 1.7. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 21

22 1.7 Factors affecting drug release 43 Figure 1.7: Schematic illustration of the mechanism of drug release by erosion from tablet The study on the drug release from the hydrophilic matrices requires knowledge of properties and interaction of the polymers used as the binder Polymer hydration Polymer dissolution includes absorption/adsorption of water in more accessible place, rupture of polymer polymer linking with the simultaneous formation of water polymer linkage, separation of polymeric chain, swelling, and finally, dispersion of polymeric chain in the dissolution medium. Methocel K polymer, because of low content of methoxy groups, hydrates quickly, which justifies its application in controlled release matrices. Larger size fraction of HPMC hydrates more rapidly than smaller fraction. The first few minutes of hydration are the most important because they correspond to the time when the protective gel coat is formed around matrices containing HPMC Polymer composition The complex composition of polymer cellulose ether precedes several reactions, as hydroxyl groups, that can be reacting covalently with many species both mono and poly-functional in order to stabilize and insolubilize their structure Polymer viscosity With cellulose ether, polymer viscosity is used as an indication of the matrix weight. Increasing the molecular weight or viscosity of the polymers in the matrix formulation increases the gel layer viscosity and thus slows the drug dissolution 45. Viscosity of the gelling agent slows down or speeds up the initial process of hydration (without altering the release rate) Rekhi G.V et al 46 studied the effect on release of metoprolol tartarate from extended release formulation by using HPMC polymers of different viscosity. Vazquez M J 47 demonstrated that decreasing the matrix viscosity makes the drug diffusion SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 22

23 easier. Temperature affects HPMC hydration. With increase of gel temperature, the HPMC looses hydration property followed by decrease in relative viscosity Drug solubility Absorption of poorly soluble drugs is often dissolution rate limited. Such drugs do not require any further control over their dissolution rate. During the preformulation phase it is necessary to determine drug solubility not only in water but also at various ph. The aqueous and ph dependent solubility is important for drug release. The aqueous solubility of drug plays an important role in drug release mechanism, as soluble drugs are generally released by diffusion mechanism while insoluble drugs are released by erosion Polymer drug proportion Studies by Salomen, E Docker 48 demonstrated that the release rate increases for lower amount of HPMC with slightly soluble drug, the permeation depends on gel consistency Polymer drug interaction The evaluation of water concentration profile was calculated from HPMC matrices with different molecular weights. The thermal analysis of cellulose ether polymer demonstrated that the drug polymer interaction occurs at hydrated gel layer around the matrix tablet and is partially responsible for the drug release modulation. Ford et at 49 studied water soluble drug (promethazine hydrochloride) to evaluate the temperature effect on the drug release from matrices with several degrees of viscosity and found drug release decreases with increase of HPMC content and increase in temperature leads to increase in drug release rate. 50, Polymer swelling Thermoplastic polymers, which are sufficiently hydrophilic, are water soluble. A sharp advancing front divides the unpenetrated core form a swollen and dissolving shell. Under stationary conditions, a constant thick surface layer is formed by the swollen polymer and by a high concentration polymer solution. If the dissolution occurs normally, the steady-state surface layer consists of four different sub layers as liquid sub layer (adjacent to the pure solvent) gel sub layer, solid swollen sub layer and infiltration sub layer (adjacent to the polymer), gel sub layer, solid swollen sub layer and filtration sub- layer (adjacent to the polymer base into which the solvent has not yet migrated). The dissolution rate strongly depends on hydrodynamic conditions, temperature, polymer molecular weight and crystalline level 52. Although outwardly simple, drug release from hydrophilic matrices is a complex phenomenon resulting from the interplay of many different physical processes. In short, drug SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 23

24 release from these systems is the consequence of controlled matrix hydration, followed by gel formation, textural/ rheological behavior, matrix erosion, and/ or drug dissolution and diffusion, the significance of which depends on drug solubility and concentration and changes in matrix characteristics as illustrated in figure , 54. At the molecular level, drug release is determined by water penetration, polymer swelling, drug dissolution, drug diffusion and matrix erosion. These phenomena depend upon the interaction among water, polymer, matrix content and the drug. Water has to penetrate the polymer matrix, leading to polymer swelling and drug dissolution, before the drug can diffuse out of the system. In effect, water decreases the glass transition temperature of the polymer to the experimental temperature resulting in a transformation of the glassy polymer into a rubbery phase. The enhanced mobility of the polymeric chains favors the transport of water and consequently of the dissolved drug 55.. Figure 1.8: water concentration gradient, textural behavior and polymer drug concentration gradient in swelling polymer matrix Tablet hardness and density Valasco MV et al 56 evaluated effect of compression force on drug release from HPMC matrices and reported independence of drug release with compression force on drug release from HPMC matrices. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 24

25 1.7.9 Effect of diluents Addition of water soluble diluent like lactose and water insoluble diluent like tri basic calcium phosphate, showed difference in the release profile, This is because of the difference in the solubility of the diluents and their subsequent effect on the tortuosity factor. As water soluble diluents dissolve, they diffuse outward and decrease the tortuosity of the diffusion path of the drug. Tri calcium phosphate does not diffuse outward, but rather become entrapped within the matrix and affect an increase in the release of the drug by the fact that its presence necessarily decreases the gum concentration. S. Kazuhiro et al 57 investigated the effect of water soluble fillers in gel forming matrix on in vitro and in vivo drug release and observed marked difference in drug release. 58, 59, Stability studies Adequate stability data of the drug and its dosage form is essential to ensure the strength, safety, identity, quality, purity, in vitro and in vivo release rates that they claim to have at the time of use. A controlled release product should release a predetermined amount of the drug at specified time interval, which should not change on storage. Any considerable deviation from the appropriate release would render the controlled release product useless. The in vitro and in vivo release rate of controlled release product may be altered by atmospheric or accelerated conditions such as temperature and humidity. 1.9 Polymers for controlled release formulation design Even though there are a lot of different synthetic polymers, not many have been used in pharmaceutical industry especially in oral CR formulation. Most common synthetic polymers used in oral extended release/ controlled release formulation are polyvinyl alcohol (PVA), polyacrylic acid and polymethacrylate. Polyacrylic acid and its derivatives are commonly used in enteric coating due to their insolubility at low ph. Carbopol is high molecular weight cross linked poly (acrylic acid) polymer. Polymethacrylate and derivatives, mainly Eduragit. Polymers are commonly used for extended release coating 61. In pharmaceutical industry, more natural polymers or their derivatives than synthetic polymers have been used in oral CR formulations. Among the three subclasses of natural polymers, proteins, polysaccharides, and nucleotides, only polysaccharides are widely used in oral extended release/ controlled release formulations. Cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxylpropylcellulose (HPC), hydroxyethylcellulose (HEC), ethyl cellulose (EC) are the most SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 25

26 commonly used polymers in oral CR formulations 62, 63. For each cellulose derivative, different grades can also have significantly different properties in terms of molecular weight, viscosity, solubility, hydration etc. Different grades can be used for different purposes. Besides cellulose derivatives, many polysaccharides especially dietary fibers have been used in drug development. table 1.5 lists the commonly used natural polymers or their derivatives in oral ER formulations. Polymers used in dissolution controlled release systems are different than the polymers used in diffusion controlled systems. The polymers in diffusion controlled systems are generally water insoluble. Some commonly used polymers for diffusion - controlled systems (reservoir and monolithic systems) are cellulose (e.g., ethylcellulose), collagen, nylon, poly (alkyl cyanoacrylate) polyethylene, poly (ethylene co vinyl acetate), poly (hydroxyethyl methacrylate), poly (hydroxypropylethyl methacrylate) poly (methylmethacrylate) polyurethane, and silicon rubber. Table 1.4: Common natural polymers and derivatives used in oral ER formulation Polymer Hydroxypropyl cellulose Hydroxypropylmethyl cellulose Ethyl cellulose Methyl cellulose Carboxymethyl cellulose Sodium Sodium alginate Chitosan Xanthan gum Comment Used in matrix extended release formulation Widely Used in matrix extended release formulations Insoluble in water. Is widely used in coating for extended release applications. Also used in matrix tablets for diffusion controlled CR formulation, 64, 65. that is, lipophillic matrix Not as efficient as HPMC and HPC in slowing down drug release rate Sometimes used in matrix tablets together with HPMC and HPC in slowing down drug release rate Besides thickening, gel forming, and stabilizing properties, it can also easily gel in the presence of a divalent cation such as Ca 2+ ph dependent hydrogelation of chitosan matrixes Good alternative for cellulose polymer SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 26

27 1.9.1 Polymer properties For polymers used in oral ER formulations, there are several important properties that can influence formulation design especially drug release rate, as shown in table 1.6. Besides drug release kinetics, polymer properties can also affect process development. Other polymer properties such as flowability, compatibility, and so on are also very important in process development. Table 1.5 Polymer properties versus drug release mechanism Mechanism Dissolution Diffusion Osmosis Ion Exchange Polymer property Polymers such as HPMC, soluble in water molecular weight, viscosity, hydration speed and so on Lipophilic polymers, such as ethyl cellulose, poly(methylmethacrylate) ploy (hydroxyethyl methacrylate), insoluble in water molecular weight viscosity, lipophilicity, and so on that can affect drug diffusion through them Semi permeable membranes such as cellulose acetate water permeability through them Cross linked resins 1.10 Hot melt granulation technology Melt granulation/extrusion technology represents an efficient pathway for manufacture of drug delivery systems. Industrial application of the extrusion process dates back to Mostly it has been used in the plastic, rubber and food industry 67. Recently melt granulation has found its place in pharmaceutical manufacturing operations 68. The potential of the technology is reflected in the wide scope of different dosage forms including oral dosage forms, implants, bioadhesive ophthalmic inserts, topical films, and effervescent tablets. In addition, the physical state of the drug in a granulate/extrudate can be modified with the help of process engineering and the use of various polymers. Melt granulation is now widely used in pharmaceutical research for the enhancement of dissolution of poorly soluble drugs and for modifying the release of the drug. Melt granulation is a process by which pharmaceutical powders get converted to granule form by the use of a binder which can be a molten liquid, a solid or a solid that melts during the process. The drug can be present in crystalline form for sustain release applications or dissolved in a polymer to SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 27

28 improve dissolution of poorly water-soluble drugs 69. The possible use of a broad selection of polymers starting from high molecular weight polymers to low molecular weight polymers and various plasticizers has opened a wide field of avenues for formulation research. Melt granulation process is currently applied in the pharmaceuticals for the manufacture of variety of dosage forms and formulation such as immediate release and extended release pellets, granules and tablets. This process can be used for the preparation of extended release dosage forms by using lipophillic binders such as glyceryl monostearate 70, a combination of hydroxypropyl methylcellulose and hydrophobic polymers. Advantages Solvents are not used in this process. Processing steps are few and time consuming drying step is eliminated. Good stability at varying ph and moisture levels. Process is relatively simple, continuous and efficient. Limitations Process requires high-energy input. Process requires heating therefore best suited for thermostable drugs. Low melting point binders are generally used in melt granulation technique, they are at times difficult to handle as they may soften during storage. High melting point binders, if used, require high temperature for melting this causes instability problem for heat labile materials Main applications in Pharmaceutical Industry For improving the dissolution rate and bioavailability of the drugs by forming a solid dispersion e.g., Polyethylene glycol is used as the dissolution enhancer in griseofulvin tablets and in turn that improvises the bioavailability. Controlling or modifying the release of the drug e.g., spirapril hydrochloride tablets or metformin hydrochloride tablets with hydrogenated vegetable oil and stearic acid 71, 72, 73. To mask the bitter taste of the active drug e.g., Antibiotics such as cefpodoxime proxetil 74 with stearic acid coating Materials used in the system Two types of meltable binders are used frequently in melt granulation systems, hydrophilic and hydrophobic. The temperature range in which they should melt is very critical from the processing viewpoint. Hydrophilic meltable binders normally melt between C. Polyethylene glycol has been widely used in melt granulation because of its favorable solution SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 28

29 properties, low melting point, rapid solidification rate, low toxicity and low cost 75. Poloxamers like copolymers of ethylene oxide and propylene oxide which are low melting solids, can be used for melt granulation technology. Gelucire is a mixture of glycerides and fatty acid esters of PEGs. It increases the dissolution rate of poorly water soluble drugs which is attributed to surface active and self emulsifying properties 76 and hydrophobic meltable binders usually melt between C and listed in table 1.7. Table 1.6: List of Meltable binders Meltable binders Melting range ( C ) Hydrophilic meltable binders Polyethylene glycols Poloxamer 188, 237, 338 or Gellucire Hydrophobic meltable binders Stearic acid Stearic alcohol Hydrogenated castor oil Glyceryl stearate Glyceryl behenate Glyceryl palmitostearate Hydrogenated vegetable oils Glyceryl monosterate Beeswax Carnauba wax Paraffin wax Techniques for melt granulation Melt granulation technique involves agitation, kneading and layering the active in the presence of a molten binding liquid. Dry granules are obtained as the molten binding liquid solidifies on cooling. The equipments for the melt granulation include rotating pans, fluid bed processer, low or high shear jacketed mixer etc. During the melt granulation process, the meltable binder may be added as molten liquid or as the dry flakes. In the later, the binder can be heated by hot air or by a heating jacket to above SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 29

30 the melting point of the binder. Alternatively, the melt granulation process involves an extremely high shear input where due to the high shear heat of friction alone raises the temperature of the binder and effects binding. Typically, the melting points of the meltable binders range from C. There are various technologies available for the melt granulation Melt agglomeration Melt agglomeration is a process by which the fine solid particles are bound together into agglomerates by agitation, kneading and layering, in the presence of a molten binding liquid which solidifies on cooling. Typical examples of melt agglomeration processes are melt pelletization and melt granulation. During the agglomeration process, a gradual change in the size and shape of the agglomerates would take place. It is usually not possible to clearly distinguish between granulation and pelletization. Thus granulation is considered a pelletization process when highly spherical agglomerates of narrow size distribution are produced. The equipment for melt agglomeration include rotating drums or pans, fluid bed granulators, low-shear mixers such as Z-blade and planetary mixers, high shear mixers Agglomeration by distribution In agglomeration by distribution mode, distribution of molten binding liquid on the surface of the particles will occur and agglomerates are formed via coalescence between the wetted nuclei. Agglomeration by immersion In agglomeration by immersion mode, nuclei are formed by immersion of the primary particles onto the surface of the droplet of the molten binding liquid. Primarily, the distribution of molten binding liquid to surfaces of nuclei has to be effected by densification prior to coalescence between the nuclei. Depending on the relative size between the solid particles and the molten binding liquid droplets, the distribution will be a dominant mode when the molten binding liquid droplets are smaller than the solid particles or of a similar size. On the other hand, the immersion mode will dominate when the molten binding liquid droplets are larger than the solid particles. A molten binding liquid of low viscosity promotes the distribution mode of agglomeration. In the case of immersion, it is more favorable for molten binding liquid of high viscosity, which could resist breaking by dispersive forces. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 30

31 Spray congealing Spray congealing is a melt technique of high versatility. In addition to manufacture multiparticulate delivery system, it can be applied to process the low meltable materials into particles of defined size and viscosity values for the melt agglomeration process. Processing of meltable materials by spray congealing involves spraying a hot melt of wax, fatty acid, or glyceride into an air chamber below the melting point of the meltable materials or at cryogenic temperature. Spray-congealed particles ( µm in diameter) are obtained upon cooling. The congealed particles are strong and nonporous as the solvent is evaporated. Ideally, the meltable materials should have defined melting points or narrow melting ranges. Viscosity modifier, either meltable or non-meltable at the processing temperature, may be incorporated into the meltable matrix to change the consistency of the molten droplets. Tumbling melt granulation A newer melt agglomeration technique, i.e., tumbling melt granulation, for preparing spherical beads has been reported. A powdered mixture of meltable and non-meltable materials is fed onto the seeds in a fluid-bed granulator. The mixture adheres onto the seeds with the binding forces of a melting solid to form the spherical beads. In preparing the spherical beads, both viscosity and particle size of the meltable materials should be kept at an optimum value. The particle size of a meltable material should be 1/6 or lower than the diameter of the seeds. High-viscosity meltable materials should not be employed to avoid agglomeration of seeds and producing beads of lower size. Melt extrusion technology represents an efficient pathway for manufacture of drug delivery systems. Resulting products are mainly found among semi-solid and solid preparations. The potential of the technology is reflected in the wide scope of different dosage forms including oral dosage forms, implants, bioadhesive ophthalmic inserts, topical films, and effervescent tablets. In addition, the physical state of the drug in an extrudate can be modified with help of process engineering and the use of various polymers. The drug can be present in crystalline form for extended release applications or dissolved in a polymer to improve dissolution of poorly water-soluble drugs. The possible use of a broad selection of polymers starting from high molecular weight polymers to low molecular weight polymers and various plasticizers has opened a wide field of numerous combinations for formulation research. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 31

32 1.11 Multiparticulate unit dosage forms Oral controlled release drug delivery systems can be classified into two broad groups. Single unit dosage forms (e.g., tablets or capsules) and multiple unit dosage forms (e.g. pellets, granules or microparticles). Although similar drug release profiles can be obtained with both dosage forms, multiple unit dosage forms offer several advantages. The multiparticulates spread uniformly throughout the gastrointestinal tract. High local drug concentrations and the risk of toxicity due to locally restricted tablets can be avoided. Premature drug release for enterically coated dosage forms in the stomach, potentially resulting in the degradation of the drug or irritation of the gastric mucosa, can be reduced with coated pellets because of a more rapid transit time when compared to enterically coated tablets. Better distribution of multiparticulates along the GI-tract could improve the bioavailability, which potentially could result in a reduction in drug dose and side effect. Inter and intra-individual variations in bioavailability-caused, for example, by food effect are reduced. With coated single dose dosage forms, the coating must remain intact during the drug release phase; damage to the coating would result in a loss of the extended release properties and dose dumping. If not compressed, the mechanical strength of the coating of pellets is not as critical as with tablets since unwanted dose dumping from pellets is practically nonexistent. Various drug release profiles can be obtained by simply mixing pellets with different release characteristics. In addition, a more rapid onset of action can be achieved easier with pellets than with tablets as shown in figure 1.9. Figure 1.9: Drug release profile of matrix and multiparticulate dosage form With regard to the final dosage form, the multiparticulates can be filled in hard gelatin capsules or be compressed in to tablets. SPP School of Pharmacy and Technology Management, SVKM s NMIMS, Mumbai 32