PRINCIPLES OF DRUG RELEASE IN VARIOUS DOSAGE FORMS

World Journal of Pharmaceutical Research Reddy et al. World Journal of Pharmaceutical Research SJIF Impact Factor 5.045 Volume 3, Issue 4, 426-439. Review Article ISSN 2277 – 7105 PRINCIPLES OF DRUG RELEASE IN VARIOUS DOSAGE FORMS K.Venkata Ramana Reddy1*, Dr. B.Venkateswara Reddy2, P.Shruti1 1 Dept.of Pharmaceutics, Sree Dattha Institute of Pharmacy, R.R.District. Andhra Pradesh 501506, India. 2 Dept.of Pharmaceutics, St.Pauls College of Pharmacy, Turkayamzal, R.R.District. Andhra Pradesh - 501506, India. ABSTRACT Article Received on 15 April 2014, Revised on 08 May 2014, Accepted on 01 June 2014 Among various dosage forms parenteral dosage form stands in first place to exert its action in individuals and next to this in current day‟s aerosol and nasal dosage forms competent to parenteral route. Drug release may follow mixed mechanism of release; it may involve both *Correspondence for diffusion and dissolution controlled processes. The drug release is Author function of excipients, in which the drug is embedded or covalently K.Venkata Ramana Reddy bound. Dept.of Pharmaceutics, Sree Dattha Institute of Pharmacy, type of excipients, their concentration, method of manufacturing, physico-chemical properties of drugs and excipients, R.R.District. Andhra Pradesh - design of dosage form (geometry), routes of administration, 501506, India. pharmacokinetic and physico-dynamic parameters of drug. Morphological characteristics such as porosity, tortuosity, surface area, and shape of the system. Hydrophilicity/hydrophobicity of the system, chemical interaction between drug and polymer, polymer characteristics such as glass transition temperature and molecular weight .It is not always correct to show the same type of release in all dosage forms with same excipients and is going to vary and depend upon release the all above parameters to subject optimization. Key Words: Physico-Chemical Properties of Drug and Excipients, Various Dosage Forms. INTRODUCTION Parenteral delivery Syringeability and injectability are closely related. Syringeability is the ability of a parenteral solution or suspension to pass easily through a hypodermic needle from the storage vial to injection, such as ease of withdrawal, tendency for clogging and foaming, and accuracy of www.wjpr.net Vol 3, Issue 4, 2014. 426 Reddy et al. World Journal of Pharmaceutical Research dose measurements. Injectability is the performance of the suspension during injection, involving the pressure or force required for injection, evenness of flow, aspiration qualities, and tendency of clogging. Both injectability and Syringeability are diminished with increased viscosity, density, particle size, and solids concentration. Clogging of the needle may occur due to blockage by a single particle or by the bridging effect of multiple particles (Floyd and Jain 1996). The individual particle size should be no greater than one-third of the needle‟s internal diameter (Nash 1996). Intravenous (IV) injection provides an immediate onset of action; other parenteral routes provide slower onset and/or prolonged duration. IV administration yields almost complete drug availability. IVinjected drugs are diluted in the venous system and pass through the heart, and may be eliminated by the lungs prior to entering the general circulation. This is known as the “lung first pass effect.” The fraction of drug reaching the desired sites depends on the fraction of arterial blood reaching that site (Oie and Benet 1996). Suspensions should not be administered by IV route (Robinson, Narducci, and Ueda 1996). Nano suspensions may be injected without the risk of vascular occlusion and pulmonary embolism (Floyd and Jain 1996). Intramuscular (IM) and subcutaneous (SC) injections are common routes of parenteral administration. IM preparations are injected deep into the skeletal muscles, such as the gluteal (buttocks), deltoid (upper arm), or vastus lateralis (thigh), with injection volumes of 1.5–5 mL.SC preparations are generally small volumes (<2 mL) injected into the loose interstitial tissue beneath the skin of the arm, forearm, thigh, abdomen, or buttocks. Drugs absorbed from IM or SC injection sites enter the venous blood and pass through the heart and lungs prior to entering the general circulation. This results in an initial lag period between the time of injection and time of entry into the general circulation (Oie and Benet 1996). IM and SC administrations are used for drugs that cannot be injected intravenously due to low aqueous solubility and/or when high peak concentrations result in local or systemic side effects (Zuidema et al. 1994). The rate of drug release and absorption depends on the physicochemical properties of the drug, formulation variables, and injection and physiological factors. Hydrophilic drugs in aqueous systems are absorbed more rapidly in smaller injection volumes due to greater diffusional potential. Lipophilic drugs in oily vehicles are absorbed more rapidly in smaller injection volumes, again due to greater diffusional potential. Absorption of lipophilic drugs in aqueous vehicles increases with increased injection volume. (Zuidema et al. 1994) www.wjpr.net Vol 3, Issue 4, 2014. 427 Reddy et al. World Journal of Pharmaceutical Research Suspensions that contain smaller particles have faster dissolution rates, due to the increased surface area of the particles (Hirano and Yamada 1982) However; particle aggregation may reduce the dissolution rate, due to increased effective surface area, increased viscosity, and altered rheology. Suspensions of larger particles have slower dissolution rates and provide sustained drug release and prolonged action. Increasing drug concentration may lead to aggregation and reduced dissolution and absorption rates. Excipients, such as surfactants, may reduce aggregation and increase the dissolution and absorption rates. Altering the suspension vehicle may affect the dissolution and absorption rates. Increased viscosity reduces the diffusion coefficient and dissolution rate. It is important for the drug to remain in solution at the injection site for absorption. This is not a problem for oily systems because the rate of clearance of the oily vehicle is generally slower than the rate of absorption of the drug. . Precipitation of drugs may occur at the injection site following the absorption of the aqueous vehicle and change in pH (Zuidema et al. 1994). Absorption generally occurs by passive diffusion. Other mechanisms for drug absorption from parenteral administration include phagocytosis by macrophages or lymphatic transportation. Drug uptake by the lymphatic system is mostly achieved by SC or intra peritoneal (IP) injection. The absorption pathway of injected drugs depends on injection depth, lipophilicity, and size of particles or carrier. Molecules smaller than 5 kDa favor absorption into capillaries. Molecules larger than 16 kDa and particles or liposomes larger than 200 nm are preferentially drained into the lymphatic system (Zuidema et al. 1994). The intensity and duration of drug activity depend upon the physicochemical and pharmacokinetic properties of the drug, degree of plasma protein binding, extent of distribution throughout the body, and rate of elimination by metabolism and/or excretion (Robinson, Narducci, and Ueda 1996). Depot injections are controlled release formulations (either aqueous suspensions or oleaginous solutions) injected into subcutaneous or muscular tissues. The depot formed at the injection site acts as a drug reservoir providing prolonged drug release and duration of action (Chien 1992c). Depot injections provide constant and sustained drug levels; reduce the frequency of injection, dose required and side effects; and improve patient compliance. www.wjpr.net Vol 3, Issue 4, 2014. 428 Reddy et al. World Journal of Pharmaceutical Research The processes involved in the drug release from an IM drug depot include diffusion of water to the depot, dissolution of suspended drug particles, diffusion in the dispersing agent, drug transfer from oily vehicles into water phase, and diffusion away from the depot to the systemic circulation (Zuidema 1988). The rate of drug release from depot formulations is controlled by dissolution, adsorption, encapsulation, and esterification. Reduced dissolution may be provided by increasing the size of suspended particles. Respiratory Delivery Inhalation is noninvasive and non traumatic, and it avoids the risk of transmitting bloodborne pathogens, encountered with parenteral injections Particle size and distribution are key elements in aerosol drug delivery and efficacy of drugs delivered by the pulmonary route. Deposition in the respiratory tract occurs by five main physical mechanisms: inertial impaction, sedimentation, diffusion, interception, and electrostatic deposition (Gonda 1990). Deposition by inertial impaction occurs due to the momentum of the aerosol particles. Particles with higher mass or velocity have longer stopping distances and increased chances of deposition on the walls of the respiratory tract. Generally, larger particles (above 5 µm) with high velocity are deposited in the back of the mouth and upper airways by inertial deposition (Gonda 1992). Deposition by sedimentation is governed by Stokes‟ law. Smaller particles (0.5 to 3 µm) are deposited in the bronchial and alveolar regions by sedimentation (Brain and Blanchard 1993). Increased sedimentation occurs during either breath holding or slow tidal breathing (Gonda 1992). Deposition by diffusion is due to Brownian motion, caused by constant random collisions of gas particles with small aerosol particles. Aerosol deposition by diffusion is independent of particle density but increases with decreasing particle size. It is dependent upon residence time and enhanced by breath holding. In general, inertial impaction and sedimentation dominate the deposition of particles larger than 1 µm and diffusion dominates the deposition of particles smaller than 0.1 µm. For the size range between 0.1 and 1 µm, both sedimentation and diffusion are important (Brain and Blanchard 1993). Deposition by interception generally occurs for elongated particles. Electrostatic deposition occurs for charged particles. Drug deposition is affected by the aerosol characteristics, breathing patterns, and airway caliber (Newman and Clarke 1983) Greater aerosol deposition www.wjpr.net Vol 3, Issue 4, 2014. 429 Reddy et al. World Journal of Pharmaceutical Research into the lung periphery occurs with lower MMAD and higher proportion of particles below 5 µm (Dolovich 1992). Size enlargement of aerosol droplets or particles may occur in the respiratory tract, due to hygroscopic growth (Gonda 1990; Gonda and Byron 1978; Hickey and Martonen 1993). Other aerosol characteristics, such as particle shape, influence aerosol deposition. The breathing pattern of the patient may influence aerosol deposition (Newman and Clarke 1983; Martonen and Katz 1993). Factors include inspiratory airflow rate, respiratory volume, respiratory frequency, and breathe holding duration at the end of inspiration. Airway geometry affects aerosol deposition (Newman 1985). Variations in airway geometry are due to differences in gender, lung volume, age, and disease state (Brain and Blanchard 1993; Newhouse and Dolovich 1986). Drug absorption in the respiratory tract occurs mainly by passive diffusion (Gonda 1990), by which absorption is determined by molecular size and lipophilicity. Other absorption routes include transport through aqueous pores, carrier-mediated active transport processes, and lymphatic transport (Gonda 1990; Thompson 1992). DPI powder formulations require drug particles to have aerodynamic diameters below 5 µm for lung deposition. Respirable-sized drug particles may be prepared by either size reduction through milling or particle construction through condensation, evaporation, or precipitation. Such particles generally exhibit poor flow properties due to their high inter particle forces. Formulation strategies to improve the flowability of respirable particles include the controlled agglomeration of drug particles or adhesion onto excipients carrier particles in the form of interactive mixtures (Hersey 1975). Aerosol dispersion of the drug particles from aggregates or interactive mixtures is required for lung deposition (Ganderton 1992). The aerosol dispersion depends upon the particle interactions within the powder formulation and the mechanical forces of dispersion from the device. Strong inter particulate forces within the powder formulation may lead to poor efficiency (Byron 1986). Factors affecting particle adhesion and aerosol dispersion of DPI formulations include physicochemical properties of the drug and carrier, such as size, shape, surface roughness, chemical composition, polymorphic form and crystalline state, the drugcarrier ratio, and the presence of ternary components (Crowder et al. 2001; Dunbar, Hickey, and Holzner 1998a). www.wjpr.net Vol 3, Issue 4, 2014. 430 Reddy et al. World Journal of Pharmaceutical Research Drug particle size Drug particle size affects aerosol dispersion: Smaller particles produce lower fine-particle fraction (FPF) of drug-alone formulations, due to higher cohesion, whereas larger particles are less cohesive but more likely to deposit in the upper stage due to inertial impaction. Surface modification by adhesion of nanoparticles onto the drug particles may increase aerosol dispersion of drug-alone and carrier based formulations (Kawashima et al. 1998a, 1998b). The particle size of carrier particles can influence aerosol dispersion. Drug deposition is generally observed with smaller carrier size and increased proportion of fine particles. Nasal Delivery Nasal deposition mainly depends on particle or droplet size, airflow rate, and nasal geometry. Inhaled particles are deposited mainly by inertial impaction. Translocation by mucociliary clearance results in a secondary deposition of the drug .Nasal absorption and bioavailability are affected by the physicochemical properties of the drug, such as molecular weight (MW), solubility and dissolution rate, pK a and partition coefficient, degree of ionization, particle size and morphology, and polymorphic state (Behl et al. 1998). The nasal absorption of drugs with MW less than 300 Da is not significantly influenced by the other physicochemical properties of the drug. Increased molecular weight above 300 Da reduces absorption. The rate of absorption also depends on physiological factors, such as rate of nasal secretion, ciliary movement, and metabolism. Reduced bioavailability is observed with increased rate of nasal secretion and mucociliary clearance. Drug metabolism in the nasal cavity is minimal, due to the fast absorption rate and relatively short exposure time of enzymes and the low levels of enzymes that are present. The effect on absorption for most compounds, except peptides, is insignificant. Nasal powders and gels are less commonly used, although both may prolong contact time with the nasal mucosa. Nasal suspensions are not commonly used due to the limited amount of water available in the nasal cavity for dissolution. For particulate nasal products (dry powders or suspensions), the dissolution rate of the drug affects the absorption rate. Particles deposited in the nasal cavity generally must be dissolved prior to absorption. If drug particles are cleared before absorption, bioavailability is reduced. The particle size, morphology, and polymorphic state affect dissolution and absorption (Behl et al. 1998). www.wjpr.net Vol 3, Issue 4, 2014. 431 Reddy et al. World Journal of Pharmaceutical Research Buccal and Sublingual Delivery The buccal mucosa has a thickness of 600 µm, a surface area of 50 cm2, and a turnover of 13 days. The sublingual mucosa has a thickness of 200 µm, a surface area of 26 cm, and a turnover of 20 days. The sublingual membrane is more permeable than the buccal membrane (Burkoth et al. 1999). Limitations include the difficulty of maintaining dosage forms at the sublingual or buccal sites, lack of penetration of some drugs, and the small surface area available for drug absorption. Preparations used for buccal or sublingual delivery include tablets, lozenges, liquid capsules, and aerosols Drug transport across the oral mucosa occurs through the transcellular and paracellular routes. Absorption occurs mainly by passive diffusion. Drug absorption is affected by the lipid solubility, partition coefficient, molecular weight, solubility at site of absorption, and degree of ionization (Chien 1992b; Lamey and Lewis 1990). High potency is required for effective drug administration from buccal and sublingual routes, due to the limited surface area for absorption (Lamey and Lewis 1990) Oral Delivery Drug absorption following oral administration may be limited by drug instability and poor intrinsic membrane permeability, resulting in inefficient and erratic drug therapy. The rate of drug absorption depends on the physicochemical properties of the drug, formulation factors, and physiological conditions (Table 9.1). Physicochemical properties of the drug that affect its absorption include the solubility and dissolution rate, oil/ water partition coefficient (Ko/w), degree of ionization (determined by the pKa of the drug and pH of the biological fluid), and the molecular weight (Mayersohn 1996). Drugs with a higher K o/w have increased membrane permeability. Non ionized drugs also have greater membrane permeability. Weakly acidic drugs have higher permeability when the pH is less than the pKa, whereas weakly basic drugs have high permeability when the pH is greater than the pKa. However, most drugs are absorbed from the small intestine, regardless of degree of ionization. The dissolution rate from solid dosage forms and the residence times of the drug in different regions of the gastrointestinal tract affect drug absorption. However aggregation of small particles may increase the effective surface area, resulting in unchanged or reduced dissolution rate and bioavailability. Reduced aggregation of drug particles and increased dissolution rates may be obtained by using solid dispersions and interactive mixtures, drug aggregation and reduced dissolution rate have been observed with increased drug concentration within interactive mixtures. The addition of ternary surfactants reduces drug aggregation and increases dissolution rate. Changes in particle size may be minimized by selection of particles with www.wjpr.net Vol 3, Issue 4, 2014. 432 Reddy et al. World Journal of Pharmaceutical Research narrow size ranges, more stable crystalline forms (higher melting points), avoidance of high energy milling (reduced amorphous content), use of a wetting agent to dissipate the free surface energy of particles, use of protective colloids (gelatin, gums) to form a film barrier around particles to inhibit dissolution and crystal growth, increased viscosity to retard particle dissolution, and avoidance of extreme temperature fluctuations (Nash 1996). Drug Release from Hydrophilic Matrices The mechanism of drug release from hydrophilic matrix tablets after ingestion is complex but it is based on diffusion of the drug through, and erosion of, the outer hydrated polymer on the surface of the matrix. Typically, when the matrix tablet is exposed to an aqueous solution or gastrointestinal fluids, the surface of the tablet is wetted and the polymer hydrates to form a gelly-like structure around the matrix, which is referred to as the “gel layer”. This process is also termed as the glassy to rubbery state transition of the (surface layer) polymer. This leads to relaxation and swelling of the matrix which also contributes to the mechanism of drug release. The core of the tablet remains essentially dry at this stage. In the case of a highly soluble drug, this phenomenon may lead to an initial burst release due to the presence of the drug on the surface of the matrix tablet. The gel layer (rubbery state) grows with time as more water permeates into the core of the matrix, thereby increasing the thickness of the gel layer and providing a diffusion barrier to drug release. In case of matrix tablets if the drug is coated with a soluble coating, so drug release relies solely on the regulation of drug release by the matrix material. If the matrix is porous, water penetration will be rapid and the drug will diffuse out rapidly. A less porous matrix may give a longer duration of release. Unfortunately, drug release from a simple matrix tablet is not zero order. The Higuchi equation describes the release rate of a matrix table. So the drug release rate is regulated by the permeability of the membrane as well as the matrix. The film becomes porous after dissolution of the soluble part of the film. An example of this is the combined film formed by ethyl cellulose and methylcellulose. Close to zero-order release has been obtained with this type of release mechanism. Gum-Type Matrix Tablets Some excipients have a remarkable ability to swell in the presence of water and form a substance with a gel-like consistency. When this happens, the gel provides a natural barrier to drug diffusion from the tablet. Because the gel-like material is quite viscous and may not disperse for hours, this provides a means for sustaining the drug for hours until all the drug www.wjpr.net Vol 3, Issue 4, 2014. 433 Reddy et al. World Journal of Pharmaceutical Research has been completely dissolved and has diffused into the intestinal fluid. A common gelling material is gelatin. However, gelatin dissolves rapidly after the gel is formed. Drug excipients such as methylcellulose, gum tragacanth, veegum, and alginic acid form a viscous mass and provide a useful matrix for controlling drug dissolution. Drug formulation with these excipients provides sustained drug release for hours. The most important consideration in this type of formulation appears to be the gelling strength of the gum material and the concentration of gummy material. Polymeric Matrix Tablets The number of polymers available for drug formulations is increasing and includes polyacrylate, methacrylate, polyester, ethylene–vinyl acetate copolymer (EVA), polyglycolide, polylactide, and silicone. Of these, the hydrophilic polymers, such as polylactic acid and polyglycolic acid, erode in water and release the drug gradually over time. A hydrophobic polymer such as EVA releases the drug over a longer duration time of weeks or months. The rate of release may be controlled by blending two polymers and increasing the proportion of the more hydrophilic polymer, thus increasing the rate of drug release. The addition of a low-molecular-weight polylactide to a polylactide polymer formulation increased the release rate of the drug and enabled the preparation of an extended-release system. Hydrophobic polymers with water-labile linkages are prepared so that partial breakdown of the polymers allows for desired drug release without deforming the matrix during erosionSoluble drugs can be released by a combination of diffusion and erosion mechanisms whereas erosion is the predominant mechanism for insoluble drugs [1]. For successful extended release of drugs, it is essential that polymer hydration and surface gel layer formation are quick so as to prevent immediate tablet disintegration and premature drug release. For this reason, polymers for hydrophilic matrices are usually supplied in small particle size (such as Methocel CR grades) to ensure rapid hydration and consistent formation of the gel layer on the surface of the tablet. A large number of mathematical models have been developed to describe drug release profiles from matrices [2-7]. The simple and more widely used model is the one derived by Korsmeyer et al. [8] Mt / M α = k t www.wjpr.net n --------------- (1) Vol 3, Issue 4, 2014. 434 Reddy et al. World Journal of Pharmaceutical Research Where Mt / M a is the fraction of drug release, k is the diffusion rate constant, t is the release time and n is the release exponent indicative of the mechanism of drug release. The equation was modified by Ford et al. to account for any lag time or initial burst release of the drug Mt / M a = k (t – 1) n -------------- (2) Where l is the lag time. It is clear from both equations that when the exponent n takes a value of 1.0, the drug release rate is independent of time. This case corresponds to zero-order release kinetics (also termed as case II transport). Here, the polymer relaxation and erosion [9], is the rate-controlling steps. When n= 0.5, Fickian diffusion is the rate-controlling step (case I transport). Values of n between 0.5 and 1 indicate the contribution of both the diffusion process as well as polymer relaxation in controlling the release kinetics (non-Fickian, anomalous or first-order release). It should be noted that the two extreme values of n= 0.5 and 1 are only valid for slab geometry. For cylindrical tablets, these values range from 0.45 < n< 0.89 for Fickian, anomalous or case II transport respectively[10]. Drug release by matrix solubilization Materials in this category include currently used enteric coatings, which can generally be classified as polyacids. In their un-ionized form, they are water-insoluble, but upon ionization of their carboxylic acid groups, they become more water-soluble. Some of the most widely studied systems are partially esterified copolymers of methyl vinyl ether and maleic anhydride or partially esterified copolymers of ethylene and maleic anhydride[11-14]. In a constant pH environment, esterified polymers undergo a controlled dissolution process and are, therefore, useful materials for the controlled release of therapeutic agents dispersed within them. Transdermal and Topical Delivery Drugs delivered transdermally must penetrate the skin in sufficient quantities to exert a systemic effect without being affected by enzymes in the epidermis (Robinson, Narducci, and Ueda 1996). Therapeutic potency is required with doses of less than 10 mg .The surface area of the skin is approximately 2m2. The pH of the skin ranges between 4.8 and 6.0 (Ramachandran and Fleisher 2000). The elimination half-life should not be too short, to avoid having to apply the patch more www.wjpr.net Vol 3, Issue 4, 2014. 435 Reddy et al. World Journal of Pharmaceutical Research frequently than once a day. The solubility of drug in the skin rather than the concentration of drug in the patch layer is the most important factor controlling the rate of drug absorption through the skin The blood flow rate is about 0.05 mL/min/mm3 and is altered by physiological and psychological responses, such as intradermal powder injections use a supersonic gas flow to accelerate drug particles through the skin at high velocities (300–900 m/s). The entrained drug particles penetrate through the stratum corneum and deposit in the epidermis. The depth of penetration is directly related to the particle size, density, and velocity, which is controlled by nozzle design and gas pressure. The injected drug particles dissolve within the epidermis and diffuse to their intended site of action, either local or systemic. Intradermal powder injection was shown to give results similar to subcutaneous needle injection (Burkoth et al. 1999). Fig 1: Types of transdermal drug delivery system (TDDS) with their parts There are two basic designs of the patch system that dictate drug release characteristics and patch behavior: (i) matrix or monolithic and (ii) reservoir or membrane. In the matrix system [15-20], the inert polymer matrix binds with the drug and controls its release from the device. In the reservoir system, the polymer matrix does not control drug release. Instead, a ratecontrolling membrane present between the drug matrix and the adhesive layer provides the rate-limiting barrier for drug release from the device. Types of transdermal drug delivery system(TDDS) with their parts were displayed in above figure 1. Transdermal System is examples of reservoir-type patch systems. Each type of patch design has its advantages and disadvantages. While reservoir systems offer true zero-order (constant) drug release rates, drug release rates from matrix systems undergo a slight decline over time because of progressive increase in length of the diffusional pathway as the drug is being depleted from the system. However, with most well-designed matrix systems, this decline is insignificant and provides a pseudo zero-order or apparently constant drug release rate during the designated period of patch use. With the reservoir system, there is a tendency for the drug www.wjpr.net Vol 3, Issue 4, 2014. 436 Reddy et al. World Journal of Pharmaceutical Research molecules to diffuse into the control membrane over time and saturate it. If these patches are stored on the pharmacy shelf for a long time before use, it is possible for the patient to experience a „burst effect‟ attributed to initial release of a large amount of drug from the patch and subsequent absorption into the skin. The burst effect may be advantageous for drugs that normally exhibit a considerable lag time between patch application and therapeutic effect. Regardless of the design, most patches are intended to deliver drug into the skin at a constant rate over a designated period of time. Since drug diffusion occurs passively according to fick‟s law, the rate of flux remains constant (zero-order) as long as the concentration gradient across the barrier is unchanged. In other words, there needs to be a significantly large amount of drug in the device in order to maintain a uniform concentration gradient over the duration of patch use. When drug concentrations in the patch are depleted significantly, the drug release rate begins to drop, and the zero-order rate is no longer maintained. Most patches should be removed before reaching this stage. The needle-free injection is painless and allows patient self-administration. Additionally, powder formulations provide greater storage stability. Local tissue reactions include mild and transient erythema. Physicochemical properties of the drug and formulation may affect drug penetration and absorption. The particle size and size distribution affects drug penetration. Drug penetration occurs with particles larger than 20 µm. Particles with reduced density (porous or hollow particles) have reduced penetration. Particle shape and surface morphology do not appear to affect drug delivery. The particles must be strong enough to withstand particle–particle and particle–wall collisions in the helium gas jet. Physiological factors affecting drug absorption include dissolution characteristics, pH profile during dissolution, local osmotic pressure, local tissue binding, and drug metabolism (Burkoth et al. 1999). CONCLUSION The bottom line of this article entitles significance of all excipients with their marking role towards designing of various dosage forms having impact on drug release directly. Not only excipients even design of dosage forms, nature and type of drug with solubility profile, physico-chemical properties of drug ,compatibility of excipients with drug, pharmacokinetic and dynamic properties of drug, half life, protein binding and molecular weight of polymers. www.wjpr.net Vol 3, Issue 4, 2014. 437 Reddy et al. World Journal of Pharmaceutical Research REFERENCES 1. Rajabi-Siahboomi, A.R. and Jordan, M.P. (2000) slow release HPMC matrix systems. Eur Pharm Rev, 5, 21–23. 2. Siepmann, J., Kranz, H., Bodmeier, R. and Peppas, N.A. (1999) HPMC-matrices for controlled drug delivery: a new model combining diffusion, swelling, and dissolution mechanisms and predicting the release kinetics. Pharm Res, 16, 1748–1756. Siepmann,3 3. J. and Peppas, N.A. (2000) Hydrophilic matrices for controlled drug delivery: an improved mathematical model to predict the resulting drug release kinetics (the “sequential layer” model). Pharm Res, 17, 1290–1298. 4. Siepmann, J. and Peppas, N.A. 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