Quality Control Tests for Liquid Dosage Forms PDF

Quality control tests for Oral liquid dosage forms Dr Javed Qureshi Liquid oral • Liquid orals are the pharmaceutical dosage form in liquid form containing one or more active ingredients with or without additives dissolved in a suitable vehicle to be administered orally either in the form of solu...

Quality control tests for Oral liquid dosage forms Dr Javed Qureshi Liquid oral • Liquid orals are the pharmaceutical dosage form in liquid form containing one or more active ingredients with or without additives dissolved in a suitable vehicle to be administered orally either in the form of solution, suspension, emulsions, elixir and many more. Types of liquid dosage forms Type of oral liquids • Syrup: “In medical terminology, medicinal syrups are nearly saturated solutions of 85% of sugar in water in which medicinal substances or drugs are dissolved.” • Elixirs: “Elixir are clear, flavored Oral Liquids containing one or more active ingredients dissolved in a vehicle that usually contains a high proportion of sucrose or a suitable polyhydric alcohol or alcohols and may also contain Ethanol (95 per cent) or a dilute Ethanol.” contd • Suspensions : “Suspensions are Liquids containing one or more active ingredients suspended in a suitable vehicle. Suspended solids may slowly separate on keeping but are easily redispersed”. • Emulsions : “An emulsion is defined as a dibasic or heterogenous liquid preparation immiscible liquids which is dispersed as a minute globules in another liquid by adding emulsifying agent. IPQC for liquid dosage forms CLEAN AND PURIFIED VEHICLE (WATER):- The water is filtered and purified at the plant to destroy any microorganisms and to remove particles from the water. Water is tested frequently to ensure that it is clean and pure before the preparation • Quality control technicians test the water frequently to ensure that it is clean and pure. • Volume in container Ensure that the final pack contain the desired volume. Organoleptic properties (Appearance) Visual examination: • The ingredients and the final products are carefully examined for purity and for appearance. Physical appearance of products for patient adherence and compliance is critical so it should be Good looking, Elegant in appearance. pH MEASUREMENT:pH of the oral liquid preparations must be optimum as per the pharmacopoeial standards and limits of pH . pH is a measure of the hydrogen ion activity is important from the standpoint of stability and physiological suitability of drug and dosage form. The determination is carried out at a temperature of 25±2°C, unless otherwise specified in the individual monograph. Assay • To detect the strength of API by using suitable analytical method to produce good finished pharmaceutical. Uniformity of volume • This test is suitable for oral liquids and oral suspensions of viscous preparations. For this test select a sample of 10 filled containers and determine the weight of the contents of each container. Determine the weight per ml and calculate the net volume of the content of each container. • For non-viscous and free-flowing liquids pour completely the contents of each container into calibrated volume measures of the appropriate size and determine the net volume of the contents of the 10 containers. • Limits : The average net volume of the contents of the 10 containers should not be less than the labeled amount, and the net volume of the contents of any single containers should not less than the percentage deviation as shown in Table. Net Volume (mL) 50 or less 50-200 mL 200-300 mL Percentage deviation 9% 5.5 % 3% • If this requirement is not met, determine the net volume of the contents of 10 additional containers. • The average net volume of the contents of the 20 containers is not less than the labeled amount and the net volume of the contents of not more than 1 of the 20 containers is deviating from the limits as mentioned in table. SYRUP Concentration of Syrup According to B.P: 67.7% W/W According to USP: 85% W/V Components of syrup • Sweetening Agent: Sucrose, Sugar. • Antimicrobial Preservatives: Benzoic acid, Sodium benzoate, Methyl-, propyl-, and butyl-parabens. • Flavorings agents: Orange oil, Vanillin and others. • Colorants: green with mint, chocolate with brown etc. • Alcohol (15 to 20%) [if alcohol soluble components are present in syrup] • Purified water Quality evaluation of Syrup • Visual inspection/ Physical appearance. • Light transmission matter/ Colour. • PH measurement. • Physical stability in syrups. • Sucrose concentration. • Weight per ml. • Viscosity. • Optical rotation • Solubility. • Assay of active ingredient LIGHT TRANSMITTANCE TEST (Color examination • In a light transmittance meter, a liquid sample is checked for colour by passing light through the sample. The percent of light transmission is compared to light transmission rates set for different grades. • No fingerprints on test bottle and should not have bubbles or cloudiness, Any of these conditions may diminish the light that is transmitted through the sample and therefore lowers the grade of the sample. pH measurement • Generally, plain syrup does not require pH adjustment. Only medicated syrups require pH adjustment in the range of 3 to 6. This is because general medicaments (drugs) are stable in acidic pH. Hence to ensure the stability of drugs in syrup up to the defined shelf life (expiry period) the pH of medicated syrups is adjusted. • For antacids like Aluminum hydroxide, Magnesium hydroxide the inherent pH of these drugs (salts) is alkaline and hence medicated syrups containing these antacid drugs have pH at the alkaline side (more than 8 to 10) to ensure the stability of formulations up to shelf life. Physical stability in syrups • The syrups must be stable physically e.g. • • • • its appearance (no crystallization and microbial growth) Color must be completely soluble with other ingredients. Odor and taste (palatable) Solid material is completely miscible in liquid. • DETERMINATION OF SUCROSE CONCENTRATION (FOR SYRUPS ONLY):- If the concentration of Sucrose in the syrup is very high it may crystallize the syrup, less sucrose concentrations give favor for the microbial growth. For the determination sucrose in syrup, HPLC and UV -spectroscopy are used. Optical rotation: Range is 50°-60°. Syrup should not be less than 50° & not more than 60°. It is to check the inversion of syrup Specific gravity: Specific gravity of syrup either 66.7% w/w or 85% w/v should be 1.313. Elixirs Elixirs are clear, sweetened hydro-alcoholic solutions intended for oral use and are usually flavored to enhance their palatability. Evaluation Parameters: Determination of alcohol content: Elixir usually contains 5 to 40% alcohol. For liquids, it is presumed to contain less than 30% of alcohol. DETERMINATION OF VISCOSITY: • Viscosity is a property of liquids that is directly related to the resistance to flow. • viscosity measurement is very important quality control test in case of syrups an elixirs. • viscosity and consistency directly relates with stability of solutions. • Determination of viscosity is done to assess the changes that might take place during aging. • The viscometers used are cone and plate viscometers , Brookfield viscometer . BIPHASIC LIQUIDS: EMULSIONS SUSPENSIONS Emulsion • An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases, one of which is dispersed as globules ( the dispersed phase) in other liquid phase ( the continuous phase) stabilized by the presence of an emulsifying agent. CLASSIFICATION OF EMULSIONS:- Emulsions can be classified into the following types:- 1. Oil in water (o/w) type of emulsion. 2. Water in oil (w/o) type of emulsion. 3. Microemulsions ( 0.01 to 0.2 mm, Thermodynamically stable) 4. Macroemulsion ( 0.2 to 50 mm, Kinetically stable) 5. Nano emulsion ( 10-1000 nm, Kinetically stable) 6. Multiple/double emulsion. (o/w/o, w/o/w) Kinetically stable /thermodynamically stable • Nanoemulsions are kinetically stable" means liquids in the mixture will become separated very slowly. But the separation will happen eventually. • "Microemulsions are thermodynamically stable" means the separation won't happen even waiting for a very-very long time. • Kinetic stability refers that from the reactant state (emulsion) to the product state (separated liquids) the reaction barrier is very high, but the free energy change is still negative (ΔG < 0). However, thermodynamic stability means the free energy change from the reactant state to the product state are positive (ΔG > 0), which means the reaction will not happen if there is no external energy input. Identification Tests • Since emulsion (o/w or w/o) looks the same in appearance with naked eyes, therefore certain tests have been developed to differentiate between them. At least two tests should be done to reach a conclusive decision about the identity of the emulsion. • Conductivity Test • Dye Solubility Test • Dilution test • Cobalt Chloride Test • Fluorescence Test DILUTION TEST:- • This test is based on the solubility of external phase of emulsion. • o/w emulsion can be diluted with water. • w/o emulsion can be diluted with oil. Conductivity Test: The basic principle of this test is that water is a good conductor of electricity. Therefore, in case of o/w emulsion this test will be +ve as water is the external phase. Bulb = Bulb glows with O/W = Bulb doesn’t glow with W/O Electrode Emulsion In this test, an assembly is used in which a pair of electrodes connected to an electric bulb is dipped into an emulsion. If the emulsion is o/w type, the electric bulb glows. DYE SOLUBILITY TEST • When an emulsion is mixed with an oil soluble dye such as amaranth and observed under the microscope. • If the continuous phase appears red, then it means that the emulsion is o/w type as water is the external phase. • If the scattered globules appear red and continuous phase is colour less, then it is w/o type. DYE TEST Fluorescence test Principle: When oils are exposed to ultraviolet radiations they get fluorescence Test: A small quantity of sample emulsion is allowed to exposing to ultraviolet radiations and observes the results. Observations A fluorescent droplets are observed against colorless background indicating the type of emulsion is oil in water (O/w) emulsion or fluorescent background against colorless droplets indicating the type of emulsion is water in oil (w/o)emulsion Cobalt chloride test • When a filter paper soaked in cobalt chloride solution is dipped into an emulsion and dried, it turns from blue to pink, indicating that the emulsion is o/w type. Stability of Emulsion What is called a stable emulsion? A system in which the globules retain their initial character & remain uniformly distributed throughout the continuous phase. The three (3) major problems associated with physical stability of emulsion are: 1. Creaming or sedimentation (upward or downward movement of dispersed droplets in continuous phase). 2. Cracking (aggregation or coalescence of dispersed droplets to reform separation). 3. Phase inversion (O/W invert to become a W/O and vice versa) Flocculation • This process refers to aggregation of the droplets (without any change in primary droplet size) into larger units. • Flocculation occurs when there is not sufficient repulsion to keep the droplets apart to distances where the van der Waals attraction is weak. • Flocculation may be ‘‘strong’’ or ‘‘weak,’’ depending on the magnitude of the attractive energy involved Creaming / sedimentation Creaming is the rising (upward creaming) or settling (downward creaming) of floccules to form a concentrated layer at the surface or at the bottom of the emulsion. Its a reversible instability which can be restored by simple agitation It can be observed by a difference in colour shade of the layers. Creaming or Sedimentation This process results from external forces usually gravitational or centrifugal. When such forces exceed the thermal motion of the droplets (Brownain motion), a concentration gradient builds up in the system with the larger droplets moving faster to the top (if their density is lower than that of the medium) or to the bottom (if their density is larger than that of the medium) of the container This is not a serious instability problem as a uniform dispersion can be re-obtained simply by shaking the emulsion. (It’s a reversible process). Disadvantages: • 1.Inelegant in appearance. • 2.Possibility of inaccurate dosage. • 3.Increase probability of globules coalescence Factors affecting creaming : These factors are described in Stoke’s Law as follows: V = d2 (ρ1 – ρ2) g / 18 η • • • • V is the velocity of creaming d = diameter of globule/ particles ρ1 = density of the particle/globule, ρ2 = density of the vehicle, (ρ1 – ρ2) is the density difference of the disperse phase & dispersion medium • η is the viscosity of the dispersion medium. Creaming is decreased by: • Reduction in globule size (using homogenizer). • Decrease in the density difference between two phases. • Increase the viscosity of the continuous phase (use thickening agent as methyl cellulose). Viscosity measurement • As the viscosity increases flocculation of globules will be reduced simultaneously the Brownian movement of globules will also be hindered leading to creaming. • Due to this antagonistic effect an optimum viscosity is desirable for good emulsion stability. Globule size • As the globule size is reduced they tend to exhibit Brownian movement. • According to stokes law the diameter of the globule is considered as a major factor in creaming of emulsion. • The rate of creaming decreases four folds when the globule diameter is halved. • So it is necessary to choose the optimum globule size for maximum stability. Globule size distribution • Globules of uniform size impart maximum stability. • In such emulsions globules pack loosely and globule to globule contact is less. • Globule distribution is affected by viscosity, phase volume ratio, density of phases etc. • An optimum degree of size distribution range should be chosen to achieve maximum physical stability Globule size determination • Microscopic examination of globule size distribution analysis is a useful tool to evaluate the physical stability. Ostwald Ripening (Disproportionation) • This results from the finite solubility of the liquid phases. • Liquids that are referred to as being immiscible often have mutual solubilities that are not negligible. With emulsions, which are usually polydisperse, the smaller droplets will have larger solubility when compared with the larger ones • With time, the smaller droplets disappeared, and their molecules diffuse to the bulk and become deposited on the larger droplets. With time, the droplet size distribution shifts to larger values. Ostwald ripening Coalescence • Coalescence is followed by creaming stage. It’s an irreversible damage to emulsion. • In this process the emulsifier film around the globules is destroyed to a certain extent. Globules tends to fuse together and forms bigger globules • This step can be recognized by increased globule size and reduced number of globules. • Cracking can be caused by any chemical, physical or biological effect that changes the nature of the interfacial film of an emulsifying agent tends to make unstable. Coalescence is observed due to a) insufficient amount of the emulsifying agent b) altered partitioning of the emulsifying agent c) incompatibilities between emulsifying agents d) Change in temperature e) Presence of micro-organism Factors causing coalescence 1. Addition of opposite type emulsifying agent: Example: 1.Soaps of monovalent metals produce o/w emulsions while soaps of divalent metals produce w/o emulsions. Addition of a monovalent soap to a divalent emulsions, or addition of divalent soaps to monovalent emulsions leads to cracking of emulsions. 2. Addition of anionic and cationic emulsifying agents in same emulsion may leads to cracking of emulsions, because they are mutually incompatible. 2. Decomposition or Precipitation of emulsifying agents. • Alkali soaps are decomposed by acids, hence addition of acetic acid solution to turpentine oil liniment results precipitation of soft soap leads to cracking of emulsions. • Addition of alcohol to the emulsions prepared with gums and the proteins results precipitation of emulsifying agents leads to cracking of emulsions, because these are incompatible with alcohol. 3. Addition of common solvent Addition of liquid in which both dispersed phase and dispersion medium are soluble forms one phase system and destroys the emulsion ex: Addition of sufficient alcohol to turpentine liniment results clear solution because alcohol dissolves soft soap, water and turpentine oil. 4. Microbial action Emulsions not intended for immediate use should contain preservative to prevent growth of moulds and bacteria that might over a long period destroy the emulsifying agent and cause cracking of emulsions. Incorporation of excess dispersed phase In a given space the maximum concentration of dispersed phase can be incorporated into the ideal emulsion is not greater than 74%. Emulsions with a dispersed phase concentration in excess of 74% have a marked tendency to crack the emulsion. Creaming Keeping creaming condition of emulsion for longer duration of time may leads to cracking of emulsions. Phase Inversion Phase inversion is the result of inverting O/W emulsion into W/O emulsions or W/O emulsion into O/W emulsion. It is mainly due to following reasons. 1. Addition of a substance that alters the solubility of the emulsifying agent Ex: An o/w emulsion stabilized with Na stearate can be inverted to w/o type by adding Ca Cl2 To form Ca stearate. Ex: Addition of monovalent metal soaps to W/O emulsions or addition of Divalent soaps to O/W emulsion results in phase inversion: 2. Phase volume ratio • Phase inversion may also be produced by alterations in phase-volume ratio (i.e the proportion or concentration of dispersed phase in continuous phase). • The most stable range of disperse phase concentration is 30 to 60%. Incorporation of higher concentration may lead to phase inversion. Chemical Stability 3 types • Oxidation • Microbial Contamination • Adverse storage conditions. • Causes: Change in pH, fluctuation in storage condition, presence of light in case of light sensitive products, oxidative decomposition Oxidation • Many of the oils and fats used in emulsion are of animal or vegetable sources and can be susceptible to oxygen by the atmospheric oxygen or by the action of microorganism • Microbial oxidation can be controlled by antimicrobial agents • Atmospheric oxidation can be controlled by the addition of antioxidant like BHA (butylatedhydroxyanisole) Microbial contamination • Adversely affect the physicochemical properties of the product: gas production, color and odor changes, hydrolysis of fats and oil, pH change and breaking of emulsion. • w/o products have less chance of microbial spoilage • Commonly used antimicrobial are Mehtyl paraben and Propyl paraben Adverse storage condition • Adverse storage condition may also cause emulsion instability. • Increase in temperature increases the rate of creaming due to decreased viscosity of continuous phase • Increasing in temperature causes increase in kinetic motion of both dispersed phase and emulsifying agent which results in more expanded monolayer so coalescence is more likely. • Freezing of aqueous phase produces ice crystal which may exert a pressure on disposed globule and on emulgent layer. In addition the dissolved electrolyte will concentrate in unfrozen water therefore changing the charge density on globules. Which leads to cracking • Certain emulgent may also get precipitate at low temperature •EVALUATION OF SUSPENSION Viscosity measurement • Stability of a suspension is solely dependent on the sedimentation rate of dispersed phase which is dependent on the viscosity of the dispersion medium. • The viscosity of the dispersion medium is measured before mixing with dispersed phase and also viscosity after mixing is determined using Brook field viscometer. • The calculated values are compared with standard values and if any difference is found necessary corrective action is taken to get optimized viscosity. Particle size determination • DETERMINATION OF PARTICLE SIZE:- It is performed by optical microscopy and Coulter counter apparatus. Principle of Coulter counter In a COULTER COUNTER instrument, a tube with a small aperture on the wall is immersed into a beaker that contains particles suspended in a low-concentration electrolyte. Two electrodes, one inside the aperture tube and one outside the tube but inside the beaker, are placed and a current path is provided by the electrolyte when an electric field is applied. The impedance between the electrodes is then measured. The aperture creates what is called a "sensing zone". Particles in low concentration, suspended in the electrolyte, can be counted by passing them through the aperture. As a particle passes through the aperture, a volume of electrolyte equivalent to the immersed volume of the particle is displaced from the sensing zone. This causes a short-term change in the impedance across the aperture. This change can be measured as a voltage pulse or a current pulse. The pulse height is proportional to the volume of the sensed particle. Principle of coulter counter Principle of optical microscopy • This method for particle characterization can generally be applied to particles not less than 1 μm. • The microscope eyepiece is fitted with a micrometer by which the size of the particles may be estimate Principle of optical microscopy • According to the optical microscopic method, an emulsion or suspension is mounted on ruled slide on a mechanical stage. • The microscope eyepiece is fitted with a micrometer by which the size of the particles can be estimated. • The ordinary microscope used for measurement the particle-size in the range of 0.2 to about 100 µm Brownian movement • Brownian movement of particles prevents sedimentation. • Brownian movement can be observed, if the size of the particle is about 2 to 5μm,provided densities of the particles and viscosity of the medium are favorable. • Theory of Brownian movement proposes particle size and viscosity as the major factors. • Brownian movement depends on the density of dispersed phase and the density and viscosity of the disperse medium. • The kinetic bombardment of the particles by the molecules of the suspending medium will keep the particles suspending, provided that their size is below critical radius (r). STABILITY OF SUSPENSIONS:SEDIMENTATION • Sedimentation means settling of particle (or) floccules occur under gravitational force in liquid dosage form. • Velocity of sedimentation expressed by Stoke’s equation Limitations of Stokes law: • Stokes’ law is based upon several assumptions, which may not always hold true for pharmaceutical suspensions. The law has following limitations: • Valid for only diluted pharmaceutical suspensions that are composed of no more than 2% solids. • Considers only free particle settling of particles without interference • Considers all particles are spherical (Stokes law assumes spherical and monodisperse particles, which may not be encountered in real system) • Stokes’ equation is invalid if the density difference in the equation is negative that is when the particles are lighter than the dispersion medium • not valid for high content of dispersed solids: When the solid content of a suspension is high, Stokes’ equation may not show the real sedimentation rate. High solid content imparts additional viscosity to the system, which must be taken into consideration if the correct rate of settling is to be determined. The equation contains only the viscosity of the medium. Application of stokes law Stokes law is useful in fixing factors to prevent sedimentation. • Particle size: If the particle size is reduced to half of its original size the rate of sedimentation decreases by a factor of four. • Viscosity of medium: The viscosity of suspension should be optimum. • Density of the medium: The density of medium should be high so that the difference in densities will be minimal. • The density of medium can be increased by including ingredients such as polyvinyl pyrrolidine, sugars, polyethylene glycols, glycerin etc. Sedimentation parameters Sedimentation volume (F) or height (H) for flocculated suspensions: Sedimentation volume is a ratio of the ultimate volume of sediment (Vu) to the original volume of sediment (VO) before settling. F = V u / VO Where, • Vu = final or ultimate volume of sediment • VO = original volume of suspension before settling Sedimentation volume The sedimentation volume gives only a qualitative account of flocculation. • F has values ranging from less than one to greater than one. When F < 1 Vu < Vo When F =1 Vu = Vo • The system is in flocculated equilibrium and show no clear supernatant on standing. When F > 1 Vu > Vo • Sediment volume is greater than the original volume due to the network of flocs formed in the suspension and so loose and fluffy sediment • A suspension consisting of floccules held together loosely will have large β, while suspension containing sediment has small β. • The lower limit of β is equal to 1; which means there is no flocculation, i.e., vu = v∞ • How can you induce flocculation? • You can do that by use of flocculating agents, such as electrolytes, detergents and polymers. • Flocculating agents are agents that are added to the medium to promote flocculation by counter acting the effect of protective layer the thus decrease zeta potential. Degree of flocculation (β) • It is the ratio of the sedimentation volume of the flocculated suspension ,F , to the sedimentation volume of the deflocculated suspension, F∞ ß = F / F∞ 𝞫= 𝑉𝑢/𝑉𝑜 𝑓𝑙𝑜𝑐𝑐𝑢𝑙𝑎𝑡𝑒𝑑 (𝑉𝑢/𝑉𝑜)𝑑𝑒𝑓𝑙𝑜𝑐𝑐𝑢𝑙𝑎𝑡𝑒𝑑 • The maximum value of ß is 1,when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension. Electrokinetic properties • Electrical Double layer • Zeta potential • DLVO theory Electrokinetic properties • Zeta Potential: The zeta potential is defined as the difference in potential between the surface of the tightly bound layer (shear plane) and electroneutral region of the solution. • As the potential drops off rapidly at first, followed more gradual decrease as the distance from the surface increases. • This is because the counter ions close to the surface acts as a screen that reduce the electrostatic attraction between the charged surface and those counter ions further away from the surface • Zeta potential has practical application in stability of systems containing dispersed particles . • Since this potential, rather than the Nernst potential, governs the degree of repulsion between the adjacent, similarly charged, dispersed particles. • If the zeta potential is reduced below a certain value , the attractive forces exceed the repulsive forces, and the particles come together • The flocculated suspension is one in which zeta potential of particle is -20 to +20 mV. • Thus, the phenomenon of flocculation and de flocculation depends on zeta potential carried by particles Electrical Double layer EDL is a transition region between two phases consists of, • An inner molecular layer • A layer intermediate between inner molecular layer and the outer diffuse layer • An outer diffuse region Electrical Double Layer According to Stern, an electrical double layer consists of two parts; One part of the double layer , known as fixed part (STERN LAYER) remains almost fixed to the solid surface. It has positive or negative ions. There is a sharp fall of potential. The second part of the double layer, known as diffuse part (DIFFUSE LAYER) extends to some distance into the liquid phase. This layer contains ions of both signs. Its net charge is equal and opposite to that on the fixed part. There is gradual fall of potential into the bulk of the liquid where the charge distribution is not uniform. DLVO theory • Theory is explained by Derjaguin, Landau, Verway, Overbeek So it is known as DLVO Theory. According to this theory ,The forces on colloidal particles in a dispersion medium are due to its total potential energy function VT. VT = VA + VR VR = Electrostatic Repulsion VA= London type Vander Waals Attraction DLVO theory • DLVO theory suggests that the stability of a colloidal system is determined by the sum of these van der Waals attractive (VA) and electrical double layer repulsive (VR) forces that exist between particles as they approach each other due to the Brownian motion they are undergoing. • This theory proposes that an energy barrier resulting from the repulsive force prevents two particles approaching one another and adhering together. But if the particles collide with sufficient energy to overcome that barrier, the attractive force will pull them into contact where they adhere strongly and irreversibly together. • Therefore, if the particles have a sufficiently high repulsion, the dispersion will resist flocculation and the colloidal system will be stable. However, if a repulsion mechanism does not exist then flocculation or coagulation will eventually take place DLVO theory Thanks