product development

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Product Development ia a continuous process and comprises very initial studies like preformulation studies.

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Product Development Studies:

Product Development Studies By: Divya Kumar & Nidhi Jain School of Pharmacy, BIT Meerut

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Introduction: Prior to the development of the dosage forms, it is essential that certain fundamental physical and chemical properties of the drug molecule and other derived properties of the drug powder are determined. This information dictates many of the subsequent events and approaches in formulation development. This first learning phase is known as prefor mutation. Preforulation study commences once the drug shows significant pharmacological response in animal models and promises the possibility of same in human kind. Objective of Preformulation studies: To establish the necessary physicochemical parameters of new drug substances. To determine kinetic rate profile. To establish physical characteristics. To establish compatibility with common excipients .

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Organoleptic Property These are the Properties of compounds that can be perceived by sense organs . They may be colour , odour or taste of the compund . Colour : Color is generally a function of a drug’s inherent chemical structure relating to a certain level of unsaturation. Color intensity relates to the extent of conjugated unsaturation as well as the presence of chromophores . Some compound may appear to have color although structurally saturated. Odour : The substance may exhibit an inherent odor characteristic of major functional groups present. Odor greatly affects the flavor of a preparation or food stuff. Taste: If taste is considered as unpalatable, consideration is to be given to the use of a less soluble chemical form of the drug. The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product.

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The first step in preformulation is to establish a simple analytical method. Most drugs absorb light in the ultraviolet wavelengths (190-390 run) as they are generally aromatic and contain double bonds. The acidic or basic nature of the molecule can be predicted from functional groups. Using the UV spectrum of the drug, it is possible to choose an analytical wavelength (often Amax) suitable to quantify the amount of drug in a particular solution. Excitation of the molecule in solution causes a loss in light energy, and the net change from the intensity of the incident light (Io) and the transmitted light (I) can be measured. The amount of light absorbed by a solution of drug is proportional to the concentration (C) and the path length of the solution (L) through which the light has passed. or, Given Equation is the Beer-Lambert law, where e is the molar extinction coefficient. A= log10(Io/I) A= eCL Spectroscopy

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Solubility: Solubility may be defined as the ability of any solvent to dissolve the solute at a given standard condition. Solubility dictates the ease with which formulations for oral gavage and intravenous injection studies in animals are obtained. The pKa allows the informed use of pH to maintain solubility and to choose salts required to achieve good bioavailability from the solid state and improve stability and powder properties. A solubility of less than 1 mg mL -1 indicates the need for a salt, particularly if the drug will be formulated as a tablet or capsule. In the range 1-10 mg mLr1 serious consideration should be given to salt formation. When the solubility of the drug cannot be manipulated in this way (neutral molecules, glycosides, steroids, alcohols, or where the pKa is less than 3 for a base or greater than 10 for an acid) then liquid filling in soft or hard gelatin capsules may be necessary. Intrinsic solubility (Co) An increase in solubility in acid compared to aqueous solubility suggests a weak base, and an increase in alkali a weak acid. In both cases a dissociation constant ( pKa ) can be measured and salts should form. An increase in acidic and alkaline solubility suggests either amphoteric or zwitter ion behaviour. In this case there will be two pKas , one acidic and one basic. No change in solubility suggests a non- ionizable neutral molecule with no measurable pKa , and solubility manipulation will require either solvents or complexation .

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Dielectric Constant: The major physico - chemical properties of solutions are influenced by the solvent's dielectric constant. The dissolution of an ionic salt in a solvent depends on the dielectric constant and the polarity of the solvent and on the lattice energy changes in dielectric constant of the medium have a dominant effect on the solubility of the ionizable solute in which higher dielectric constant can cause more ionization of the solute and results in more solubilization . As an example, water ( Dw = 78.5) has higher dissociation strength on ions in comparison with ethanol (De= 24.2) which is resulted in more solubilization power of ions in water. The relation between dielectric constant and solubility can be understood by using following formula: where S1 and S2 are the solubilities of the solute in media 1 and 2; e is the charge of an electron; r is the effective radius of the ion in the medium; k is the Boltzmann constant; T is the absolute temperature ; and D1 and D2 are the dielectric constants of the media 1 and 2, respectively.

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pKa value and soubility : Seventy-five per cent of all drugs are weak bases; 20% are weak acids and only 5% are non-ionic, amphoteric or alcohols. It is therefore appropriate to consider the Henderson- Hasselbalch equations for weak bases and acids. Above Equations can be used: 1. to determine pKa by following changes in solubility 2. to predict solubility at any pH, provided that the intrinsic solubility (Co) and pKa are known 3. to facilitate the selection of suitable salt-forming compounds and predict the solubility and pH properties of the salts. Partition coefficient: It is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium.Hence these coefficients are a measure of the difference in solubility of the compound in these two solvents. Partition coefficient (the solvent:water quotient of drug distribution) has a number of applications which are relevant to preformulation :

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1. Solubility : both aqueous and in mixed solvents 2. Drug absorption in vivo: applied to a homologous series for structure activity relationships ( SAR ) 3. Partition chromatography: choice of column (HPLC ) or plate (TLC) and choice of mobile phase ( eluant ). Measruement of Partition Coefficient: P o/w = C octanol / C water Where P o/w = Partition coefficient C octanol = concentration of drug in octanol C water = concentration of drug in water K w/o (Partition coefficient) more than one indicates a lipohilic compund whil a value less than 1 indicates hydrophilic compound.

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Dissolution: Dissolution is a process by which a solid substance enters in the solvent. Dissolution rate may be defined as the amount of drug substance that goes into the solution per unit time. Theory of Dissolution: The rate of dissolution is given by Noyes and Whitney: Where, dc/ dt = dissolution rate of the drug K= dissolution rate constant C s = concentration of drug in stagnant layer C b = concentration of drug in the bulk of the solution at time t. d c  dt k (C s - C b )

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Melting Point: The melting point of a solid is the temperature at which it changes its state form solid to liquid. The melting point of a drug can be measured using three techniques : 1. Capillary melting Capillary melting gives information about the melting range but it is difficult to assign an accurate melting point . 2. Hot stage microscopy This is the visual observation of melting under a microscope equipped with a heated and lagged sample stage. The heating rate is controllable and up to three transitions can be registered. It is more precise as the phase transitions (first melt, 50% melt and completion) can be registered on a recorder as the melting proceeds, and because of the high magnification the values are more accurate. 3. Differential scanning calorimetry or thermal analysis. DTA measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate. DSC is similar to DTA, except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference, i.e. it measures the enthalpy of transition.

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Particle Size: Particle size of the particles influence variety of important factors l ike: Dissolution rate, Suspendability , Uniform distribution, Penetrability etc. Particle Size Determination can be done by following method: Sieving Microscopy Sedimentation rate method Light energy diffraction Laser holography Cascade impaction

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Sieving method : Range : 50 – 150 µm Simple, inexpensive If powder is not dry, the apertures get clogged. 2. Microscopy : Range : 0.2 – 100 µm Particle size can be determined by the use of calibrated grid background. Most direct method. Slow & tedious method. 3. Sedimentation method : Range : 1 - 200 µm Andreasen pipette is used. Particle size is calculated by stoke’s law : d st = 18 η 0 h ( ρ s - ρ 0 ) gt Where , h = distance of fall in time, t n o = viscosity of the medium ρ s = density of the particles ρ 0 = density of the dispersion medium g = acceleration due to gravity

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Light energy diffraction : Range : 0.5 – 500 µm Particle size is determined by the reduction in light reaching the sensor as the particle, dispersed in a liquid or gas, passes through the sensing zone. Quick & fast. 5. Laser holography : Range : 1.4 – 100 µm A pulsed laser is fired through an aerosolized particle spray & photographed in three dimensional with holographic camera, allowing the particles to be individually imaged & sized . 6. Cascade impaction : The principle that a particle driven by an airstream will hit a surface in its path, provide that its inertia is sufficient to overcome the drug force that tends to keep in it in airstream.

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Powder Flow Property: Powder flow properties can be affected by change in particle size, shape & density. The flow properties depends upon following- Force of friction. Cohesion between one particle to another. Fine particle posses poor flow by filling void spaces between larger particles causing packing & densification of particles.. By using glident we can alter the flow properties. e.g. Starch, Talc. By determining Angle Of Repose. A greater angle of repose indicate poor flow. It should be less than 30°. & can be determined by following equation. tan θ = h/r. where, θ = angle of repose. h=height of pile. r= radius.

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Measurement of free flowing powder by compressibility. Also known as Carr's index. CARR’S INDEX(%) =( TAPPED DENSITY – POURED DENSITY) X 100 TAPPED DENSITY It is simple, fast & popular method of predicting powder flow characteristics.

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Conclusion: Preformulation studies have a significant part to play in anticipating formulation problems and identifying logical paths in both liquid and solid dosage form technology (Fig. 8.8). The need for adequate drug solubility cannot be overemphasized. The availability of good solubility data should allow the selection of the most appropriate salt for development. Stability studies in solution will indicate the feasibility of parenteral or other liquid dosage forms , and can identify methods of stabilization. In parallel , solid-state stability by DSC, TLC and HPLC , and in the presence of tablet and capsule excipients , will indicate the most acceptable vehicles for solid dosage forms. By comparing the physicochemical properties of each drug candidate within a therapeutic group (using Cs, pKa , melting point, K%) the preformulation scientist can assist the synthetic chemist to identify the optimum molecule, provide the biologist with suitable vehicles to elicit pharmacological response , and advise the bulk chemist about the selection and production of the best salt with appropriate particle size and morphology for subsequent processing .

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