Introduction JIS

Chapter.
1
1) INTRODUCTION
1.1 Introduction to epilepsy:-
Introduction
Epilepsy (from the Ancient Greek (epilpsa) "to seize") is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, and nearly two out of every three new cases are discovered in developing countries Epilepsy is more likely to occur in young children or people over the age of 65 years; however, it can occur at any time. As a consequence of brain surgery, epileptic seizures may occur in recovering patients.
Epilepsies are classified in five ways: 1. By their first cause (or etiology). 2. By the observable manifestations of the seizures, known as semiology. 3. By the location in the brain where the seizures originate. 4. As a part of discrete, identifiable medical syndromes. 5. By the event that triggers the seizures, as in primary reading epilepsy or musicogenic epilepsy
Epilepsy is usually controlled, but cannot be cured with medication, although surgery may be considered in difficult cases. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. Not all epilepsy syndromes are lifelong some forms are confined to particular stages of childhood. Epilepsy should not be understood as a single disorder, but rather as syndromic with vastly divergent symptoms but all involving episodic abnormal electrical activity in the brain.
NIMS Institute Of Pharmacy, NIMS University Jaipur
Page 1
Chapter.1
1.2 Introduction to delivery system :-
Introduction
The oral route of drug administration is the most popular and successfully used for conventional delivery of drugs. It offers the advantages of convenience, ease of administration, greater flexibility in dosage form design, ease of production, and low cost. The parenteral route of administration is important in case of emergencies, while the topical route of drug administration recently employed to deliver drug to the specific part of the body for systemic effect. It is probable that almost 90% of all the drugs are administered by oral route. Tablets are solid preparations each containing a single dose of one or more active substances and usually obtained by compressing uniform volumes of particles. Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated. The particles consist of one or more active substances with or without excipients such as diluents, binders, disintegrating agents, glaidants, lubricants, substances capable of modifying the behaviour of the preparation in the digestive tract, colouring matter authorized by the competent authority and flavouring substances. The dosage form available for oral administrations are solutions, suspensions, powders, tablets and capsules. The physical state of most of the drugs being solid, they are administered in solid dosage form. The drugs administered by oral route are versatile, flexible in dosage strength, relatively stable, present lesser problem in formulation and packaging and are convenient to manufacturer, store, handle and use. Solid dosage forms provide best protection to drugs against temperature, light, oxygen and stress during transportation.1-3 Advantages of tablets They are unit dosage form, and they offer the capabilities of all oral dosage forms for the dose precision and the least content variability during dosing Accuracy and uniformity of drug content Optimal drug dissolution and hence, availability from the dosage form for absorption consistent with intended use (i.e., immediate or extended release). Usually taken orally, but can be administered sublingually, rectally or intravaginally.
Page 2
Chapter.1
Their cost is lowest of all oral dosage forms They are the most compact of all oral dosage forms
Introduction
They are in general the easier and cheaper to package and ship as compare to other oral dosage forms Product identification is simple and cheap, requiring no additional processing steps when employing an embossed or monogrammed punch face They are ease to administer, does not require a specialist They are better suited to large-scale production than other unit oral forms They have the better properties of chemical, mechanical and microbiological stability1,4,6
Disadvantages
Some drugs resist compression, due to their amorphous nature or low-density
Drugs having bitter taste, objectionable odour or drugs that are sensitive to oxygen may require encapsulation or coating of tablet Bioavailability problems. Chance of GI irritation caused by locally high concentrations medicament. Difficulty in swallowing tablets in a small proportion of people and so size and shape become important considerations. Slow onset of action as compared to parenteral and solution2
Types and Classes of Tablets Tablets are classified by their route of administration or functions 1. Oral tablets for ingestion Compressed tablets or standard compressed tablets Multiple compressed tablets (MCT) a) Layered tablets b) Compression coated tablets Repeat action tablets Extended release or modified release tablets Delayed action or enteric-coated tablets Film coated tablets Chewable tablets
Page 3
Chapter.1
2. Tablets used in oral cavity Buccal tablets Sublingual tablets Troches and lozenges Dental cones 3. Tablets administered by other routes Implantation tablets Vaginal tablets 4. Tablets used to prepare solutions Effervescent tablets Dispersible tablets Hypodermic tablets Tablet triturate1-3
Introduction
Page 4
Chapter.1
1.2.1 Introduction To Extended release:-
Introduction
Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability. For most unstable or toxic and have narrow therapeutic ranges. Some drugs also possess solubility problems. In such cases, a method of continuous administration of maintain fixed plasma levels as shown in Figure.
1
therapeutic agent is desirable to
Figure 1.2.1: Drug level verses time profile showing differences between zero order, controlled releases, first order extended release and release from conventional tablet2 To overcome these problems, controlled drug delivery systems were introduced three decades ago. These delivery systems have a number of advantages over traditional systems such as improved efficiency, reduced toxicity, and improved patient convenience. The main goal of controlled drug delivery systems is to improve the effectiveness of drug therapies.3 Simple definition of Extended release drug system is any drug or dosage form modification that prolongs the therapeutic activity of the drug4 Ideally an Extended release oral dosage form is designed to release rapidly some predetermined fraction of the total dose in to GI tract. This fraction (loading dose) is an amount of drug, which will produce the desired pharmacological response as promptly as possible and the remaining fraction of the total dose (maintenance dose) is then release at a constant rate. The rate of the drug absorption from the entire maintenance dose into the body should equal to the rate of the drug removal from the body by all the processes over the time for which the desired intensity of pharmacological response is required.3, 4The oral controlled-release
Page 5
Chapter.1
Introduction
system shows a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time (Extended release), thereby ensuring sustained therapeutic action. Thus, the release commences as soon as the dosage form is administered as in the case of conventional dosage forms. Controlled drug delivery is delivery of drug at a rate or at a location determined by needs of body or disease state over a specified period of time. Ideally two main objectives exist for these systems: Spatial delivery, which is related to the control over the location of drug release. Temporal drug delivery, in which the drug is delivered over an extended period of time during treatment.4,5 1.2.1.1 Disadvantages of conventional drug delivery system Inconvenient Difficult to monitor Careful calculation necessary to prevent overdosing Large amounts of drug can be lost when they dont get to the target organ Drug goes to non-target cells and can cause damage Expensive (using more drug than necessary).6 1.2.1.2 Advantages of controlled drug delivery system Avoid patient compliance problems. Employ less total drug. Minimize or eliminate local rate effects. Minimize or eliminate systemic side effects. Obtain less potentiation or reduction in drug activity with chronic use. Minimize drug accumulation with chronic dosing. Improve efficiency in treatment Cure or control condition more promptly. Improve control of condition, i.e., reduce fluctuation in drug level. Improve bioavailability of some drugs. Make use of special effects, e.g. sustained-release aspirin for morning relief of arthritis by dosing before bedtime Economy. 3,6,7 1.2. 1.3Disadvantages of controlled drug delivery system Decreased systemic availability in comparison to conventional dosage forms.
Page 6
Chapter.1
Poor in vitro - in vivo correlation.
Introduction
Possibility of dose dumping due to food, physiologic or formulation variables, chewing or grinding of oral formulations by the patient Increased risk of toxicity Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. Higher cost of formulation3,6,7,8 1.2.1.4. Terminology The conventional dosage forms are immediate release type. Non-immediate release delivery systems may be divided conveniently into three categories: Delayed Release Extended release Controlled Release Prolonged Release Site-specific and Receptor release Organ targeting Cellular targeting Sub cellular targeting7-11 1. Delayed release Delayed release systems are those systems that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Examples of delayed release system include repeat action tablets and capsules. A delayed release dosage form does not produce or maintain uniform drug blood levels within the therapeutic range. 2. Extended release system It includes any drug delivery system that achieves slow release of drug over an extended period of time. 3. Controlled release system If the system is successful at maintaining constant drug level in the blood or target tissues, it is considered as a controlled release system
Page 7
Chapter.1
Introduction
Figure1.2.2: Typical drug blood level time profiles for delayed release drug delivery by repeat action dosage form . 4. Prolonged release system If without maintaining constant level, the duration of action is extended over that achieved by conventional delivery; it is considered as a prolonged release system. This is illustrated in Fig. 2.3. 5. Site-specific and receptor release It refers to targeting of a drug directly to a certain biological location. In the case of sitespecific release, the target is a certain organ or tissue, while for receptor release; the target is the particular receptor for a drug within an organ or tissue. Both of these systems satisfy the spatial aspects of drug delivery.
Figure1. 2.3: Drug blood level time profile showing the relationship between controlled release-(a), prolonged release-(b), and conventional release-(c)
Page 8
Chapter.1
1.2.5. Principle of Extended release drug delivery
Introduction
The conventional dosage forms release their active ingredients into an absorption pool immediately. This is illustrated in the following simple kinetic scheme.
Figure1. 2.4: Kinetic scheme of conventional dosage form The absorption pool represents a solution of the drug at the site of absorption, and the term Kr, Ka and Ke are first order rate-constant for drug release, absorption and overall elimination respectively. Immediate drug release from a conventional dosage form implies that Kr>>>>Ka. Alternatively speaking the absorption of drug across a biological membrane is the ratelimiting step. For non-immediate release dosage forms, Kr<<<Ka i.e. the release of drug from the dosage form is the rate limiting step. This causes the above Kinetic scheme to reduce to the following.
Figure1. 2.5: Kinetic scheme of non-conventional dosage form Essentially, the absorptive phase of the kinetic scheme become insignificant compared to the drug release phase. Thus, the effort to develop a non-immediate release delivery system must be directed primarily at altering the release rate. The main objective in designing an extended release delivery system is to deliver drug at a rate necessary to achieve and maintain a constant drug blood level. This rate should be analogous to that achieved by continuous intravenous infusion where a drug is provided to the patient at a constant rate. This implies that the rate of delivery must be independent of the amount of drug remaining in the dosage form and constant over time.
Page 9
Chapter.1
Introduction
It means that the drug release from the dosage form should follows zero-order kinetics, as shown by the following equation: Kr = Rate in = Rate out = Ke Cd Vd.. Kr Ke Cd Vd : Zero-order rate constant for drug release-Amount/time : First-order rate constant for overall drug elimination-time-1 : Desired drug level in the body Amount/volume, and : Volume space in which the drug is distributed-Liters
The value of Ke, Cd and Vd are obtained from appropriately designed single dose pharmacokinetic study. The equation can be used to calculate the zero order release rate constant. For many drugs, however, more complex elimination kinetics and other factors affecting their disposition are involved. This in turn affects the nature of the release kinetics necessary to maintain a constant drug blood level. It is important to recognize that while zeroorder release may be desirable theoretically, non-zero-order release may be equivalent clinically to constant release in many cases. Sustained-release systems include any drug-delivery system that achieves slow release of drug over an extended period of time. If the systems can provide some control, whether this is of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered a controlled-release system.
1.2.5. Classification of sustained/controlled release systems 1.2.5.1. Extended release preparations These preparations provide an immediate dose required for the normal therapeutic response, followed by the gradual release of drug in amounts sufficient to maintain the therapeutic response for a specific extended period of time. The major advantage of this category is that, in addition to the convenience of reduced frequency of administration, it provides blood levels that are devoid of the peak-and-valley effect which are characteristic of the conventional intermittent dosage regimen. Extended release dosage forms are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action.1, 4,
11
Page 10
Chapter.1
Introduction
Table1. 2.1: Types of Extended release system Type of system Diffusion controlled Reservoir system Monolithic system Water penetration controlled Osmotic system Swelling system Chemical controlled Monolithic system Pendant system Ion exchange resins Regulated system Magnetic, Ultrasound Surface erosion or bulk erosion Hydrolysis of pendent group and diffusion from bulk polymer Exchange of acidic or basic drugs with the ions present on resins. External application of magnetic field or ultrasound to device Transport of water through semipermeable membrane Water penetration into glossy polymer Diffusion through membrane Rate-control mechanism
1.2.5.2. Controlled release preparations Although this term has been interchanged widely with Extended release preparations in the past, recently it has become customary to restrict the latter term to oral formulations where the mechanism of prolonged action is dependent on one or more of the environmental factors in the gastrointestinal tract such as pH, enzymes, gastric motility etc. On the other hand, the term controlled release dosage form usually applies to preparations that are designed for all routes of administration and where the mechanism of prolonged action is inherent and determined totally by the delivery system itself. Consequently, this category offers the current state-ofthe-art products where the drug release profile is controlled accurately and often can be targeted to a special body site or a particular organ. 1.2.6. Various approaches to achieve oral controlled release systems
The oral route of administration has received the most attention so far. This is due to easy acceptance by patients and more flexibility in the formulation. Controlled release of drugs through oral systems can be achieved by the following methods. 3
Page 11
Chapter.1
1. Diffusional controlled system
Introduction
The drug is dependent on rate of diffusion through an inert membrane barrier, usually an insoluble polymer. (a) Reservoir devices They are characterized by a core of drug, the reservoir; surrounded membrane. The nature of membrane determines the rate of drug The characteristics of reservoir diffusional system are: Core containing the drug is surrounded by polymeric membrane, which determines the rate of drug release. Zero-order delivery is possible. The drug release rate is dependent on the type of polymer. High molecular weight compounds are difficult to deliver through the devices. Coating and microencapsulation technique can be used to obtain such device. (b) Matrix devices It consists of drug dispersed homogeneously in a matrix. The characteristics of diffusional systems are: Homogeneous dispersion of solid drug in a polymer mix, Easy to produce than reservoir devices, High molecular weight compound are delivered through the devices, Zero-order release cannot be obtained. 2. Dissolution controlled systems (a) Encapsulation dissolution control Particles, seed or granules can be coated by technique such as microencapsulation or fluidized bed drier. (b) Matrix dissolution control Aqueous dispersion, congealing, spherical agglomeration techniques etc. matrix by a polymeric release.
3. Diffusion and dissolution controlled (bioerodible) In a bioerodible matrix, the drug is homogeneously dispersed in a matrix and it is released either by swelling controlled mechanism or by hydrolysis or by enzymatic attack. (a) Osmotically controlled release system Page 12
Chapter.1
Introduction
In these systems, osmotic pressure is the driving force to generate controlled release of drug. A semi-permeable membrane surrounds the drug and osmogen mixture. The drug is released at constant rate throughout GIT. i.e. pH independent release is obtained. (b) Ion-exchange systems The use of ion-exchange resin to prolong the effect of drug is based on the principle that negatively or positively charged pharmaceuticals combine with appropriate resins to yield poly-salt resonates. (c) PH independent formulation Most of the drugs are either weak bases and hence pH dependent release is observed in body fluids. However, buffers can be added to such formulations to maintain the constant micro environmental pH to obtain pH-independent drug release. 1.2.7. Introduction to matrix dosage form In this type of controlled drug delivery system, the drug reservoir results from the homogeneous dispersion of the drug particles in either a lipophilic or a hydrophilic polymer matrix.7, 11
Erosion front Zone 3 Zone 2 Zone 1 Diffusion front
Swelling front
Figure 2.6: Matrix diffusion controlled drug delivery system Zone 1: Un dissolved drug, glassy polymer layer. Zone 2: Un dissolved drug, gel layer. Gel layer thickness = Difference between erosion and swelling front position. 1.2.7.1. Introduction to hydrophilic matrix tablet A matrix tablet is a compressed dosage form containing an active ingredient, matrix agent plus fillers, lubricants and excipients. Matrix systems are highly resistant to release inconsistencies and drug dumping. A hydrophilic matrix controlled release system is relatively easy to formulate and equally important, easy to produce. It is a robust dynamic system composed of polymer wetting, hydration and dissolution. A hydrophilic matrix,
Page 13
Chapter.1
Introduction
controlled release system is a dynamic one involving polymer wetting, polymer hydration, gel formation, swelling, and polymer dissolution. At the same time, other soluble excipients or drugs will also wet, dissolve, and diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer/excipient/drug complex erodes or dissolves away. The mechanisms by which drug release is controlled in matrix tablets are dependent on many variables. The main principle is that the water-soluble polymer, present throughout the tablet, hydrates on the outer tablet surface to form a gel layer (Figure 2.7).
Ingestion of tablet
Initial wetting: Tablet surface wets and Polymer begins to hydrate, forming a gel layer, initial Expansion of the gel layer:
Water permeates into the tablet, increasing the thickness of the gel layer, soluble drugs diffuse through the gel layer.
Gel layer
Tablet erosion: Outer layer becomes fully hydrated, eventually dissolving into the gastric fluids. Water continues to permeate
Soluble drug: Is released primarily by diffusion through the
Insoluble drug: Is released primarily through tablet erosion.
Figure 2.7: Drug release from hydrophilic matrix tablet Throughout the life of the ingested tablet, the rate of drug release is determined by diffusion (if soluble) through the gel and by the rate of tablet erosion. With soluble drugs, the primary release mechanism is by diffusion through the gel layer. With insoluble drugs, the primary mechanism is by the tablet surface erosion. As increasing viscosity of the polymer yields slower drug release as a stronger more viscous gel layer is formed, providing a greater barrier to diffusion and slower attrition of the tablet, with insoluble drugs. The fine tuning of modified release systems may be achieved by blending of different viscosity grades of polymer where the desired dissolution rate is not
Page 14
Chapter.1
Introduction
obtained with a single polymer. A fast rate of hydration followed by quick gelation and polymer/polymer coalescing is necessary for a rate-controlling polymer to form a protective gelatinous layer around the matrix. This prevents the tablet from immediately disintegrating, resulting in premature drug release. Fast polymer hydration and gel layer formation are particularly critical when formulating with water-soluble drugs and water-soluble excipients. Hydrophilic matrix tablet using HPMC were prepared and evaluated by Sunada et al. They found that the type and amount of HPMC could affect the release rates as well as kinetics from the swellable matrices. Several investigators investigated the drug release rates and release kinetics from carbomer matrix tablets. Tablets exhibiting zero-order release mechanisms could be obtained at several different levels of concentration of different
carbomers, such as Carbopol 934P, 971P and 974P. The results indicated that drug release from the carbomer matrix tablets could occur, both by diffusion through low micro-viscosity pores and by a swelling-controlled mechanism. As the amount of the carbomers in their respective formulations increased, drug release rate decreased and the release mechanism gradually changed from anomalous type of release to the Case II transport mechanism. Other factors responsible for the reduction in the number and/or size of low microviscosity pores, such as higher pH that increased polymer swelling and decreased drug release, tended to shift the release profiles towards the swelling controlled, Case II type release mechanism.
1.2.7.2. Advantages of hydrophilic matrix tablets With proper control of manufacturing process, reproducible release profiles are possible. They variability associated with them is slightly less than that characterizing coated release forms. Their capacity to incorporate active principles is large, which suits them to delivery of large doses. 1.2.7.3. Disadvantages of hydrophilic matrix tablet For a hydrophilic extended release matrix tablet, in which the release is mainly controlled by erosion of the swollen polymer gel barrier at the tablet surface, the presence of food may block the pores of the matrix and inhibit the drug release rate.
Page 15
Chapter.1
The hydrophilic polymers can be arranged into three broad categories: (1) Non-cellulose natural or semi synthetic polymer
Introduction
These are products of vegetable origin and are generally used as such. Agar, alginate, guar gum, chitosan, modified starches, are commonly used polymer.
(2) Polymers of acrylic acid These are arranged in carbomer group and commercialized under the name of carbopol. The major disadvantage of this type of polymer is its pH dependent gelling characteristics.
(3) Cellulose ether This group of semi-synthetic cellulose derivatives is the most widely used group of polymer. Non-ionic such as Hydroxypropylmethylcellulose (HPMC) of different viscosity grades are widely used group of polymers. Non-ionic such as HPMC of different viscosity grades is widely used.
1.2.8. Biological factors influencing oral sustained-release dosage form design 1) Biological half-life: Therapeutic compounds with short half-lives are excellent candidates for sustained-release preparations, since this can reduce dosing frequency.3 2) Absorption: The absorption rate constant is an apparent rate constant, and should, in actuality, be the release rate constant of the drug from the dosage form. If a drug is absorbed by active transport, or transport is limited to a specific region of the intestine, sustained-release preparations may be disadvantageous to absorptions.3 3) Metabolism: Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specific period, allowing more complete conversion of the drug to its metabolite.3
Page 16
Chapter.1
Introduction
1.2.9. Physicochemical factors influencing oral sustained-release dosage form design 1) Dose size: In general, single dose of 0.5 1.0 g is considered maximal for a conventional dosage form. This also holds true for sustained-release dosage forms. Another consideration is the margin of safety involved in administration of large amounts of drug with a narrow therapeutic range.3
2) Ionization, pKa, and aqueous solubility: Most drugs are weak acids or bases. Since the unchanged form of a drug preferentially permeates across lipid membranes, it is important to note the relationship between the pKa of the compound and the absorptive environment. Delivery systems that are dependent on diffusion or dissolution will likewise be dependent on the solubility of drug in the aqueous media. For dissolution or diffusion sustaining forms, much of the drug will arrive in the small intestine in solid form, meaning that the solubility of the drug may change several orders of magnitude during its release. The lower limit for the solubility of a drug to be formulated in a Extended release system has been reported to be 0.1 mg/ml.3 3) Partition coefficient: Compounds with a relatively high partition coefficient are predominantly lipid-soluble and, consequently, have very low aqueous solubility. Furthermore these compounds can usually persist in the body for long periods, because they can localize in the lipid membranes of cells.3 4) Stability: Orally administered drugs can be subjected to both acid-base hydrolysis and enzymatic degradation. For drugs that are unstable in the stomach, systems that prolong delivery over the entire course of transit in the GI tract are beneficial. Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered from a sustaining dosage form. 3 1.2.10. Drug selection for oral extended release drug delivery systems The biopharmaceutical evaluation of a drug for potential use in controlled release drug delivery system requires knowledge on the absorption mechanism of the drug form the G. I. tract, the general absorbability, the drugs molecular weight, solubility at different pH and apparent partition coefficient.15
Page 17
Chapter.1
Table 1.2: Parameters for drug selection Parameter Molecular weight/ size Solubility Apparent partition coefficient Absorption mechanism General absorbability Release Diffusion High Preferred value < 1000 > 0.1 mg/ml for pH 1 to pH 7.8
Introduction
From all GI segments Should not be influenced by pH and enzymes
Table 1.3: Pharmacokinetic parameters for drug selection Parameter Elimination half life Comment Preferably between 0.5 and 8 h Total clearance Elimination rate constant Apparent volume of Should not be dose dependent Required for design The larger Vd and MEC, the larger will be the required dose size. Absolute bioavailability Intrinsic absorption rate Should be 75% or more Must be greater than release rate Therapeutic Css av concentration The lower Css av and smaller Vd, the loss among of drug required Toxic concentration Apart the values of MTC and MEC, safer the dosage form. Also suitable for drugs with very short half-life.
distribution Vd
Page 18
Chapter.1
Introduction
The pharmacokinetic evaluation requires knowledge on a drugs elimination half- life, total clearance, absolute bioavailability, possible first- pass effect, and the desired steady concentrations for peak and through. 1.2.11. Basic kinetics of controlled drug delivery In order to establish a basis for discussion of the influence of drug properties and the route of administration on controlled drug delivery, following mechanisms need a fair mention, - Behaviour of drug within its delivery systems - Behaviour of the drug and its delivery system jointly in the body. The first of the two elements basically deal with the inherent properties of drug molecules, which influence its release from the delivery system. For conventional systems, the ratelimiting step in drug availability is usually absorption of drug across a biological membrane such as the gastro intestinal wall. However, in sustained/controlled release product, the release of drug from the dosage form is the rate limiting instead; thus, drug availability is controlled by the kinetics of drug release than absorption.16
1.2.12. Factors influencing the in vivo performance of Extended release dosage formulations There are various factors that can influence the performance of an extended release product. The physiological, biochemical, and pharmacological factors listed below can complicate the evaluation of the suitability of an extended release dosage formulation.17 Physiological Prolonged drug absorption Variability in GI emptying and motility Gastrointestinal blood flow Influence of feeding on drug absorption Pharmacokinetic/ biochemical Dose dumping First- pass metabolism Variability in urinary pH; effect on drug elimination Enzyme induction/ inhibition upon multiple dosing
Page 19
Chapter.1
Pharmacological Changes in drug effect upon multiple dosing Sensitization/ tolerance 1.2.14. In vitro evaluation of Extended release formulation
Introduction
The data is generated in a well-designed reproducible in-vitro test such as dissolution test. The method should be sensitive enough for discriminating any change in formulation parameters and lot-to-lot variations. The key elements for dissolution are: 4 a. Reproducibility of method b. Proper choice of media c. Maintenance of sink conditions d. Control of solution hydrodynamics e. Dissolution rate as a function of pH ranging from pH 1 to 8 including several intermediate values preferably as topographic dissolution characterization. f. Selection of the most discriminating variables (media, pH rotation speed etc.) as the basis for dissolution test and specification. g. Ideal in-vitro method can be utilized to characterize bio-availability of the extended release product and can be relied upon to ensure lot-to-lot performance.4
Page 20
Chapter.1
1.3. INTRODUCTION TO DRUG:DRUG INFORMATION: 1.3.1 Drug profile Formula Mol. Mass Density Melting point Boiling point : drug -x : 250.294 g/mol :1.71 g/cm :148 - 150 C :697.3 C
Introduction
1.3.2 Physicochemical properties& description Off-White to pinkish crystalline powder Solubility: Soluble in organic solvents such as ethanol, DMSO and dimethyl formamide (solubility 20 mg/mL); slightly soluble in acetonitrile; soluble in phosphate buffered saline at-pH7.2(solubility2mg/mL) Appearance: white to slightly yellow crystalline powder 1.3.3 Pharmacokinetic data BCS class Bioavailability Metabolism Half-life Excretion Routes Drug Category Time to peak serum : I, Highly soluble : Rapidly absorbed : Hepatic :13 hours (31% to 72% longer in renal impairment) : 40% as conjugated metabolites into urine Similar amount into the faeces : Oral, intravenous : Antiepileptic : ~4 hours
Mechanism of Action The precise mechanism by which drug exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that drug-x selectively Page 21
Chapter.1
Introduction
enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyper excitable neuronal membranes and inhibition of repetitive neuronal firing. Drug-x binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown.
1.4 Pharmacokinetics Absorption and Bioavailability ANTIEPILEPTIC (DRUG-X) is completely absorbed after oral administration. The oral bioavailability of ANTIEPILEPTIC (DRUG-X) tablets is approximately 100%. Food does not affect the rate and extent of absorption. After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60minute intravenous infusions are bioequivalent to the oral tablet. Distribution The volumes of distribution are approximately 0.6 L/kg and thus close to the volume of
total body water. ANTIEPILEPTIC (DRUG-X) is less than 15% bound to plasma proteins. Metabolism and Elimination ANTIEPILEPTIC (DRUG-X) is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of 100 mg [14C]-drug-x approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The major compounds excreted were unchanged drug-x (approximately 40% of the dose), its Odesmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%). The plasma exposure of the major human metabolite, O-desmethyl-drug-x, is approximately 10% of that of drug-x. This metabolite has no known pharmacological activity. Drug-x is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-CYP enzymes in the metabolism of drug-x is not clear. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administrations. Page 22
Chapter.1
Introduction
There is no enantiomeric interconversion of drug-x Special Populations Renal impairment Drug-x and its major metabolite are eliminated from the systemic circulation primarily by renal excretion. The AUC of ANTIEPILEPTIC (DRUG-X) was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR30mL/min) really impaired patients compared to subjects with normal renal function (CLCR>80mL/min), whereas Cmax was unaffected. No dose adjustment is considered necessary in mildly and moderately renal impaired subjects. A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR30mL/min) and in patients with end stage renal disease. ANTIEPILEPTIC (DRUG-X) is effectively removed from plasma by haemodialysis. Following a 4-hour haemodialysis treatment, AUC of ANTIEPILEPTIC (DRUG-X) is reduced by approximately 50%. Therefore dosage supplementation of up to 50% following haemodialysis should be considered. In all renal impaired patients, the dose titration should be performed with caution. Side effects double vision; suicidal thoughts fast or pounding heartbeats, fluttering in your chest; feeling short of breath; fever, skin rash, swollen glands, flu symptoms; bruising, severe tingling, numbness, pain, muscle weakness; nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colour stools, jaundice (yellowing of the skin or eyes); or Lower back pain, cloudy or bloody urine, swelling, rapid weight gain, urinating less than usual. Less serious side effects may include: dizziness, spinning sensation; loss of balance or coordination; blurred vision;
Page 23
Chapter.1
nausea, vomiting; drowsiness, tired feeling; or Headache. Usual Adult Dose for Seizures: DRUG-X can be initiated with either oral or intravenous
Introduction
administration.
Initial dose: 50 mg twice daily (100 mg per day). ANTIEPILEPTIC (DRUG-X) can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient
response and tolerability. In clinical trials, the 600 mg daily dose was not more effective than the 400 mg daily dose, and was reactions. Oral ANTIEPILEPTIC (DRUG-X) may be taken with or without food. Usual Paediatric Dose for Seizures: 17year so fageand older intravenous ANTIEPILEPTIC (DRUG-X) can be initiated with either oral or Initial dose: 50 mg twice daily (100 mg per day). associated with a substantially higher rate of adverse
administration
ANTIEPILEPTIC (DRUG-X) can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability. In clinical trials, the 600 mg daily dose was not more effective than the 400 mg daily dose, and was associated with a substantially higher rate of adverse reactions. Specific Precautions and Warnings Some warnings and precautions to be aware of prior to taking ANTIEPILEPTIC (DRUG-X) include the following:
Studies suggest that seizure medications may increase the risk of suicide. Make sure to watch for any usual behaviours or mood changes, and be sure your family and friends know to keep an eye out for such problems.
ANTIEPILEPTIC (DRUG-X) can cause drowsiness, dizziness, and coordination problems. You may want to see how ANTIEPILEPTIC (DRUG-X) affects you before driving or operating heavy machinery.
Page 24
Chapter.1
Introduction
Rarely, ANTIEPILEPTIC (DRUG-X) can cause irregular heart rhythms. Be watchful for symptoms of an irregular heart rhythm, such as fainting, heart palpitations, or a rapid or slow pulse. These problems may be more likely in people with heart problems.
Seizure medications, including ANTIEPILEPTIC (DRUG-X), can cause severe allergic reactions that can affect multiple organs in the body. Let your healthcare provider know right away if you develop an unexplained rash, especially if it is accompanied by a fever.
As with all seizure medications, you should not suddenly stop taking ANTIEPILEPTIC (DRUG-X), as this can cause a worsening of seizures.
ANTIEPILEPTIC (DRUG-X) has not been adequately studied in people with liver problems. Your healthcare provider may want to monitor you more closely and might recommend a lower ANTIEPILEPTIC (DRUG-X) dosage.
Antiepileptic(drug-x) can interact with other medications ANTIEPILEPTIC (DRUG-X) is considered a pregnancy Category C medication. This means that it may not be safe for use during pregnancy, although the full risks are not currently known
It is not known if ANTIEPILEPTIC (DRUG-X) passes through breast milk in humans
Drug interactions In Vitro Assessment of Drug Interaction In vitro metabolism studies indicate that drug-x does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Drug-x did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies. In vitro data suggest that drug-x has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics. Drug-x was not a substrate or inhibitor for P-glycoprotein. Drug-x is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-CYP enzymes in the metabolism of drug-x is not clear. Since less than 15% of drug-x is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely. Page 25
Chapter.1
In Vivo Assessment of Drug Interactions Drug interaction studies with AEDs
Introduction
Effect of ANTIEPILEPTIC (DRUG-X) on concomitant AEDs: ANTIEPILEPTIC (DRUG-X) 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects. The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of ANTIEPILEPTIC(DRUG-X) at any dose. Effect of concomitant AEDs on ANTIEPILEPTIC (DRUG-X): Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day ANTIEPILEPTIC (DRUG-X). Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of ANTIEPILEPTIC (DRUG-X) in a healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in drug-x plasma concentrations when ANTIEPILEPTIC (DRUG-X) was co-administered with carbamazepine, phenobarbital or phenytoin
Drug-drug interaction studies with other drugs Digoxin There was no effect of ANTIEPILEPTIC (DRUG-X) (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects. Metformin There were no clinically relevant changes in metformin levels following co-administration of ANTIEPILEPTIC (DRUG-X) (400 mg/day). Metformin (500 mg three times a day) had no effect on the pharmacokinetics of ANTIEPILEPTIC (DRUG-X) (400 mg/day).
Page 26
Chapter.1
Omeprazole Omeprazole is a CYP2C19 substrate and inhibitor.
Introduction
There was no effect of ANTIEPILEPTIC (DRUG-X) (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that drug-x had little in vivo inhibitory or inducing effect on CYP2C19. Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of ANTIEPILEPTIC (DRUG-X) (300 mg single dose). However, plasma levels of the Odesmethyl metabolite were reduced about 60% in the presence of omeprazole. Oral Contraceptives There was no influence of ANTIEPILEPTIC (DRUG-X) (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility .There was no evidence of drug related carcinogenicity in mice or rats. Mice and rats received drug-x once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day. Drug-x was negative in an in vitro Ames test and an in vivo mouse micronucleus assay. Drug-x induced a positive response in the in vitro mouse lymphoma assay. No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the MRHD.
Page 27
Chapter.1
Introduction
1.4. INTRODUCTION TO EXCEPIENT 1.4.1 Hypromellose

1 Non-proprietary Names BP: Hypromellose JP: Hypromellose PhEur: Hypromellos USP: Hypromellose
2 Synonyms Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC;Hypromellosum;
Methocel; methylcellulose Metolose; MHPC;
propylene glycol
ether; Methyl hydroxypropylcellulose;
Pharmacoat; Tylopur; Tylose MO.
3 Chemical Names and CAS Registry Number Cellulose hydroxypropyl methyl ether [9004-65-3] 4 Empirical Formula and Molecular Weight The PhEur 6.3 describes cellulose. hypromellose as a partly O-methylated and O-(2-
hydroxypropylated) viscosity and a number solution type. By at
It is available Grades may
in several
grades. That varies in by appending aqueous substitution
extent of substitution. indicative of the
be distinguished
apparent viscosity, in mPas; of a 2% w/w specifies the
208C Hypromellose defined in the USP 32
appending a four-digit
number to
the non-proprietary name: the approximate Percentage
E.g. hypromellose 1828.The first two content of approximate CH3), groups the methoxy percentage group content of
digits refer to (OCH3). The
second two group
Digits refer to the (OCH2CH (OH) hydroxypropoxy of hypromellose;
the hydroxypropoxy
calculated on a conforming
dried basis. It contains methoxy and to the limits for the various types
Molecular weight is
approximately 10 0001 500 000
Page 28
Chapter.1
5 Structural Formula:-
Introduction
Figure1.4.1 structure of HPMC Where R is H, CH3, or CH3CH (OH) CH2 6 Functional Categories Bioadhesive material; coating agent; controlled-release agent; dispersing agent;
dissolution enhancer; emulsifying agent; emulsion stabilizer; extended-release agent; filmforming agent; foaming agent; granulation aid; modified-release agent; stabilizing agent;
mucoadhesive; release-modifying agent;
solubilizing agent;
suspending agent; sustained-release agent; tablet binder; thickening agent; viscosityincreasing agent. 7 Applications in Pharmaceutical Formulation or Technology Hypromellose is widely used in oral, ophthalmic; nasal, and topical Pharmaceutical formulations .In oral products, film-coating, and Concentrations dry-granulation as a matrix between 2% hypromellose formation a 5% w/w in is primarily used as a tablet binder, extended in
release tablet formulations.
may be
used as a binder in either wet- or
processes. High-viscosity grades may be used to retard the release of drugs 1080% w/w in tablets and capsules. Hypromellose is also
from a matrix at levels of
used in liquid oral dosage forms as ranging from 0.255.0 %.
suspending and/or thickening agent at concentrations
Depending upon the viscosity grade, concentrations forming
of 220% w/w are used for
film-
solutions to film-coat tablets. Lower viscosity
grades are used in aqueous with organic commercially the Methocel
film-coating solutions, while Hypromellose higher-viscosity grades are used solvents. Examples of film-coating materials that are and
available include Any Coat C,
Spectracel,
Pharmacoat,
Page 29
Chapter.1
E Premium LV series.
Introduction
Hypromellose is also used as a suspending and thickening
agent in topical Compared
formulations. produces aqueous solutions of preferred concentrations vehicles for eye nasal
with methylcellulose, hypromellos
greater clarity, with fewer undissolved fibers present, in formulations for
and is therefore at
ophthalmic use. Hypromellose
between 0.451.0% w/w may be added as drops and artificial tear solutions. formulations at a Hypromellose agent in topical It is
a thickening agent to also used
commercially in Liquid
concentration of is used
0.1 %. suspending agent, and Stabilizing prevent the
as an emulsifier,
gels and ointments. coalescing
As a protective Colloid, or agglomerating, hypromellose and as is used a
it can
droplets and particles from formation
thus inhibiting
of sediments. In addition,
in the manufacture wetting agent for hard
of capsules, as an adhesive in plastic bandages,
contact lenses. It is also widely used in cosmetics and food products. 10 Typical Propertie Acidity/alkalinity pH = 5.08.0 for a 2% w/w aqueous solution. Ash 41.5% Autoignition temperature 3608C Density (bulk) 0.341 g/cm3 Density (tapped) 0.557 g/cm3 Density (true) 1.326 g/cm3 Melting point Browns at 1902008C; chars at 2252308C. Glass transition temperature is 1701808C. Moisture content Hypromellose absorbs moisture from the atmosphere; the amount of water absorbed depends upon the initial moisture content and the temperature and relative humidity of the surrounding air. Solubility Soluble in cold water, forming a viscous colloidal solution; practically insoluble in hot water, chloroform, ethanol of ethanol and (95%), and ether, but soluble in mixtures dichloromethane,
dichloromethane, mixtures of methanol and
and mixtures of water and alcohol. Certain grades of aqueous acetone solutions, mixtures of
hypromellose are soluble in dichloromethane and propan-2-ol,
Page 30
Chapter.1
and other organic solvents. 1.26 Viscosity (dynamic) a available. hypromellose and wide range of viscosity types Some grades are swellable in ethanol.
Introduction
Specific gravity
are commercially
Aqueous solutions are may also be dissolved provided ethanol
most commonly prepared, although in aqueous alcohols such as ethanol 50% w/w. to prepare solvents tend
propan-2-ol and
the alcohol content is less mixtures may also using be
than used
Dichloromethane
viscous hypromellose solutions. Solutions to be more viscous; increasing
prepared
organic
concentration
also produces more viscous
solutions; To prepare an aqueous solution, it is and thoroughly hydrated in recommended that hypromellose is dispersed
about 2030% of the required amount of water. The water and then the hypromellose
should be vigorously stirred and heated to 80908C, should be added. The heat source
can be removed once the hypromellose has been Sufficient cold water should then be
thoroughly dispersed into the hot water. added
to produce the required volume while continuing to stir.
H 11. Stability and Storage Conditions Hypromellose powder is a stable material, although it is Solutions are stable at pH 311. Hypromellose transformation upon heating and 908C, depending upon the grade undergoes hygroscopic after drying. a reversible solgel
cooling, respectively. The gelation temperature is 50 and concentration of material. For temperatures below
the gelation temperature, Beyond the
viscosity of the solution decreases as temperature is increased. viscosity increases as temperature is increased. enzyme-resistant, providing good Viscosity stability aqueous solutions are liable to microbial antimicrobial preservative: when
gelation temperature,
Aqueous solutions are comparatively during long-term
storage.(15) However, preserved with an
spoilage and should be hypromellose
is used
as a Viscosity-increasing agent in ophthalmic solutions, solutions may
benzalkonium chloride is commonly used as the preservative. Aqueous
also be sterilized by autoclaving; the coagulated polymer must be redispersed on cooling by shaking. Hypromellose powder should be stored in a well-closed Container, in a cool, dry place
Page 31
Chapter.1
Table 1.4.3.: Typical viscosity values for 2% (w/v) aqueous Methocel (Dow Wolff Cellulosics) and Metolose solutions
Introduction
of
(Shin-Etsu Chemical
Co. Ltd.). Viscosities measured at 208C. Methocel and Metolose products JP/PhEur/ USP designation
Table 1.3 Typical viscosity values for 2% (w/v) aqueous solutions of Methocel
USP 28 Methocel product designa tion Methocel K100 Premium LVEP 2208
Nominal viscosity (mPa s)
100
Methocel K4M Premium Methocel K15M Premium Methocel K100M Premium Methocel E4M Premium Methocel F50 Premium Methocel E10M Premium CR Methocel E3 Premium LV Methocel E5 Premium LV Methocel E6 Premium LV Methocel E15 Premium LV Methocel E50 Premium LV Metolose 60SH Metolose 65SH Metolose 90SH
2208 2208 2208 2910 2906 2906 2906 2906 2906 2906 2906 2910 2906 2208
4000 15 000 100 000 4000 50 10 000 3 5 6 15 50 50, 4000, 10 000 50, 400, 1500, 4000 100, 400,4000,15 000
Page 32
Chapter.1
Introduction
12 Incompatibilities Hypromellose hypromellose precipitates. 13 Related Substances Ethylcellulose; hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hypromellose acetate succinate; hypromellose phthalate; methylcellulose is incompatible with some oxidizing agents. Since it is non-ionic, will not complex with metallic salts or ionic organics to form insoluble
1.4.3. Microcrystalline cellulose 1. Non-proprietary names

BP: Microcrystalline Cellulose JP: Microcrystalline Cellulose PhEur: Cellulose; Microcrystalline USPNF: Microcrystalline Cellulose
2. Synonyms Avicel PH; Cellets; Celex; cellulose gel; hellulosum microcristallinum; Celphere; Ceolus KG; crystalline cellulose; E460; Emcocel ;Ethispheres; Fibrocel; MCC Sanaq; Pharmacel; Tabulose; Vivapur. 3. Chemical name Cellulose 4. Empirical formula and molecular weight (C6H10O5) n ~36 000; where n ~ 220. 5. Structural formula
Page 33
Chapter.1
1.4.2. Microcrystalline cellulose 6. Functional category Adsorbent suspending agent Tablet and capsule diluent Tablet disintegrant. 7. Applications in pharmaceutical formulation or technology
Introduction
Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation and directcompression processes. In addition to its use as a binder/diluent, microcrystalline cellulose also has some lubricant and disintegrates properties that make it useful in tableting. Microcrystalline cellulose is also used in cosmetics and food products; Figure1.4.4:5.6 % use of concentration of MCC Use Concentration (%) Adsorbent Anti-adherent Capsule binder / diluent Tablet disintegrate Tablet binder / diluent 5 15 20 90 20 90 5 20 20 90
8. Description Microcrystalline cellulose is purified, partially depolymerized cellulose that occurs as a white, odourless, tasteless, crystalline powder composed of porous particles. It is commercially available in different particle sizes and moisture grades that have different properties and applications.
Page 34
Chapter.1
Introduction
9. Solubility Slightly soluble in 5% w/v sodium hydroxide solution Practically insoluble in water, dilute acids, and most organic solvents. 10. Typical properties Density (bulk) 0.337 g/cm3 Density (tapped) 0.478 g/cm3 Density (true) 1.5121.668 g/cm3 Melting point Chars at 2602708 C Moisture content Typically less than 5% w/w. However, different grades may contain varying amounts of water. Microcrystalline Cellulose is hygroscopic.
1.4.4 Lactose 1. Non-proprietary names BP: Lactose PhEur: Lactose Monohydrate JP: Lactose Hydrate USP-NF: Lactose Monohydrate 2. Synonyms CapsuLac; GranuLac; Lactochem; lactosum monohydricum; Monohydrate; Pharmatose; PrismaLac; SacheLac; SorboLac; SpheroLac; SuperTab 30GR; Tablettose. 3. Chemical name O-b-D-Galactopyranosyl-(1!4)-a-D-glucopyranose monohydrate 4. Empirical formula and molecular weight C12H22O11 H2O, 360.31
Page 35
Chapter.1
5. Structural formula
Introduction
1.4.3 Structure of Lactose
6. Functional category
Dry powder inhaler carrier; lyophilisation aid; tablet binder; tablet and capsule diluent; tablet and capsule filler. 7. Applications in pharmaceutical formulation or technology Lactose is widely used as a filler and diluent in tablets and capsules, and to a more limited extent in lyophilized products and infant formulas. Lactose is used as a diluent in drypowder inhalation. Usually, fine grades of lactose are used in the preparation of tablets by the wet-granulation method or when milling during processing is carried out, since the fine size allows better mixing with other formulation ingredients and utilizes the binder more efficiently. Lactose is also used in combination with sucrose to prepare sugarcoating solutions. It may also be used in intravenous injections. Lactose is also used in the manufacture of dry powder formulations for use as aqueous film-coating solutions or suspensions. Direct-compression grades are often used to carry lower quantities of drug and this permits tablets to be made without granulation. Other directly compressible lactoses are spray-dried lactose and anhydrous lactose. 8. Description Lactose occurs as white to off-white crystalline particles or powder. Lactose is odourless and slightly sweet-tasting; a-lactose is approximately 20% as sweet as sucrose, while blactose is 40% as sweet. 9. Solubility Practically insoluble in water and most other liquids, although polacrilin resins swell rapidly when wetted. Page 36
Chapter.1
Introduction
10. Typical properties. Melting point 201202 C (for dehydrated a-lactose monohydrate) Moisture content Lactose monohydrate contains approximately 5% w/w water of crystallization and normally has a range of 4.55.5% w/w water content.
1.4.5Colloidal Silicon Dioxide 1 Non-proprietary Names BP: Colloidal Anhydrous Silica JP: Light Anhydrous Silicic Acid PhEur: Silica, Colloidal Anhydrous USP-NF: Colloidal Silicon Dioxide 2 Synonyms Aerosil; Cab-O-Sil Cab-O-Sil M-5P ; colloidal silica ; fumed silica; fumed silicon anhydrica; silica sol; silicic
dioxide; Hoch disperses silicum dioxid; SAS; silica colloidalis
anhydride; silicon dioxide colloidal; silicon dioxide fumed; synthetic amorphous silica; Wacker HDK. 4 Empirical Formula and Molecular Weight SiO2 60.08 6 Functional Categories Adsorbent; anticaking agent; emulsion stabilizer; tablet disintegrate; thermal stabilizer ; glidant; suspending agent;
viscosity-increasing agent.
7 Applications in Pharmaceutical Formulation or Technology Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and food products; see Table I. Its small particle size and large specific surface area give it desirable flow characteristics that are exploited to improve the flow properties of dry powders in a number of processes such as tableting and capsule filling. Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic thickening and suspending agent in gels and semisolid preparations. With other ingredients of similar refractive index, transparent
Page 37
Chapter.1
Introduction
gels may be formed. The degree of viscosity increase depends on the polarity of the liquid (polar liquids generally require a greater concentration of colloidal silicon dioxide than nonpolar liquids). Viscosity is largely independent of temperature. However, changes to the pH of a system may affect the viscosity; In aerosols, other than those for inhalation, colloidal silicon dioxide is used to promote particulate suspension, eliminate hard settling, and minimize the clogging of spray nozzles. Colloidal silicon dioxide is also used as a tablet disintegrant and as an adsorbent dispersing agent for liquids in powders. Colloidal silicon dioxide is frequently added to suppository formulations containing lipophilic excipients to increase viscosity, prevent sedimentation during molding, and decrease the release rate. Colloidal silicon dioxide is also used as an adsorbent during the preparation of wax microspheres; as a thickening agent for topical preparations; and has been used to aid the freeze-drying of Nano capsules and Nano sphere suspensions.
Table 1.4.5: Uses of colloidal silicon dioxide. Use Aerosols Emulsion stabilizer Glidant Suspending and thickening agent Concentration (%) 0.52.0 1.05.0 0.11.0 2.010.0
8 Descriptions Colloidal silicon dioxide is sub-microscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white-colour, odourless, tasteless, amorphous powder
10 Typical Properties Acidity/alkalinity pH = 3.84.2 (4% w/v aqueous dispersion) and 3.54.0 (10% w/v aqueous dispersion) for Cab-O-Sil M-5P Density (bulk) 0.0290.042 g/cm3 Density (tapped) see Tables III, IV, and V. Melting point 16008C Moisture content see Figure 1.(12,13)
Page 38
Chapter.1
Introduction
Particle size distribution Primary particle size is 716 nm. Aerosil forms loose agglomerates of 10200 mm. See also Figure 2. Refractive index 1.46 Solubility Practically insoluble in organic solvents, water, and acids, except hydrofluoric acid; soluble in hot solutions of alkali hydroxide. Forms a colloidal dispersion with water. For Aerosil solubility in water is 150 mg/L at Specific gravity 2.2 Specific surface area 100400m2/g depending on grade. See also Tables III, IV, and V. Several Grades of 258C (pH 7).
colloidal silicon dioxide are commercially available, which Produced by modifying the manufacturing process. The modifications do not affect the silica content, Colloidal Silicon Dioxide 11 Incompatibilities Incompatible with diethylstilboestrol preparations 12 Related Substances Hydrophobic colloidal silica.
1.4.6 Talc 1 Non-proprietary Names BP: Purified Talc JP: Talc PhEur: Talc USP: Talc 2 Synonyms Altalc; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate; Imperial; Luzenac Pharma; magnesium hydrogen metasilicate; Magsil Osmanthus; Magsil Star;
powdered talc; purified French chalk; Purtalc; soapstone; steatite; Superiore; talcum. 3. Empirical Formula and Molecular Weight Talc is a purified, hydrated, magnesium silicate, approximating to the formula Mg6 (Si2O5)4(OH) 4. It may contain small, variable amounts of aluminium silicate and iron Page 39
Chapter.1
4 Functional Category
Introduction
Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant. 5 Applications in Pharmaceutical Formulation or Technology Talc was once widely used in oral solid dosage formulations as a lubricant and diluent; see Table I, although today it is less commonly used. However, it is widely used as a dissolution retardant in the development of controlled-release products. Talc is also used as a lubricant in tablet formulations; in a novel powder coating for extendedrelease pellets; and as an adsorbant. In topical preparations, talc is used as a dusting powder, although it should not be used to dust surgical gloves; see Section 14. Talc is a natural material; it may therefore frequently contain microorganisms and should be sterilized when used as a dusting powder; see Section 11. Talc is additionally used to clarify liquids and is also used in cosmetics and food products, mainly for its lubricant properties. .Table 1.4.6: Uses of talc. Use Dusting powder Glidant and tablet lubricant Tablet and capsule diluent Concentration (%) 90.099.0 1.010.0 5.030.0
6 Descriptions Talc is a very fine, white to grayish-white, odourless, impalpable, unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness.
8 Typical Properties Acidity/alkalinity pH = 710 for a 20% w/v aqueous dispersion. Hardness (Mohs) 1.01.5 Moisture content Talc absorbs insignificant amounts of water at 258C and relative humidities up to about 90%.. Particle size distribution Varies with the source and grade of material. Two typical grades Sare99% through a 74 mm (#200mesh) or 99% through a 44 mm (#325 mesh). Page 40
Chapter.1
Refractive index nD 20 = 1.541.59
Introduction
Solubility Practically insoluble in dilute acids and alkalis, organic solvents, and water. Specific gravity 2.72.8 Specific surface area 2.412.42m2/g
9 Stability and Storage Conditions Talc is a stable material and may be sterilized by heating at 1608C for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation.(10) Talc should be stored in a well-closed container in a cool, dry place, 10 Incompatibilities Incompatible with quaternary ammonium compounds
1.4.7Magnesium stearate
1. Non-proprietary names

BP: Magnesium stearate JP: Magnesium stearate PhEur: Magnesii stearas USPNF: Magnesium stearate
2. Synonyms Magnesium octadecanoate; octadecanoic acid, magnesium salt, Stearic acid, magnesium salt. 3. Chemical name Octadecanoic acid magnesium salt. 4. Empirical formula and molecular weight C36H70MgO4; 591.34 5. Structural formula [CH3(CH2)16COO]2Mg
Page 41
Chapter.1
6. Functional category Tablet lubricant. Capsule lubricant. 7. Applications in pharmaceutical formulation or technology
Introduction
Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams. 8. Description Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odour of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin. 9. Solubility Practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in warm benzene and warm ethanol (95%). 10. Typical properties Density (bulk) 0.159 g/cm3 Density (tapped) 0.286 g/cm3 Density (true) 1.092 g/cm3 Melting range 117150C (commercial samples); 126130C (high purity magnesium stearate).
Page 42

Introduction JIS

Cargado por

Información del documento

Descripción original:

Título original

Derechos de autor

Formatos disponibles

Compartir este documento

Compartir o incrustar documentos

Opciones para compartir

¿Le pareció útil este documento?

¿Este contenido es inapropiado?

Copyright:

Formatos disponibles

Introduction JIS

Cargado por

Copyright:

Formatos disponibles

Chapter.

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

therapeutic agent is desirable to

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

Soluble drug: Is released primarily by diffusion through the

Insoluble drug: Is released primarily through tablet erosion.

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

From all GI segments Should not be influenced by pH and enzymes

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

It is not known if ANTIEPILEPTIC (DRUG-X) passes through breast milk in humans

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

NIMS Institute Of Pharmacy, NIMS University Jaipur

1.4. INTRODUCTION TO EXCEPIENT 1.4.1 Hypromellose

2 Synonyms Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC;Hypromellosum;

Methocel; methylcellulose Metolose; MHPC;

ether; Methyl hydroxypropylcellulose;

Pharmacoat; Tylopur; Tylose MO.

hydroxypropylated) viscosity and a number solution type. By at

It is available Grades may

grades. That varies in by appending aqueous substitution

extent of substitution. indicative of the

apparent viscosity, in mPas; of a 2% w/w specifies the

208C Hypromellose defined in the USP 32

the non-proprietary name: the approximate Percentage

digits refer to (OCH3). The

second two group

Digits refer to the (OCH2CH (OH) hydroxypropoxy of hypromellose;

approximately 10 0001 500 000

NIMS Institute Of Pharmacy, NIMS University Jaipur

mucoadhesive; release-modifying agent;

release tablet formulations.

used as a binder in either wet- or

from a matrix at levels of

used in liquid oral dosage forms as ranging from 0.255.0 %.

suspending and/or thickening agent at concentrations

Depending upon the viscosity grade, concentrations forming

of 220% w/w are used for

solutions to film-coat tablets. Lower viscosity

grades are used in aqueous with organic commercially the Methocel

available include Any Coat C,

NIMS Institute Of Pharmacy, NIMS University Jaipur