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Dissolution Test

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Dissolution Compiled by-Shamon Ahmad Gaur Pawan Sidana and Ritika Gupta M.Pharma Q.A Chandigarh Group of Colleges Landra Mohali India email-shmmongmail.com “Dissolution tests are one of the most important quality control tests in pharmaceutical analysis. A direct relationship has been demonstrated between in vitro dissolution rate of many drugs and their bioavailability and is generally known as in vitro – in vivo correlation IVIVC”. For disintegrating solid oral dosage forms disintegration plays a vital role in the dissolution process but there is not always an automatic correlation between disintegration and dissolution especially for drugs with very low dissolution rates for which dissolution may be the rate limiting step in the absorption process”. A variety of designs of apparatus for dissolution testing have been proposed and tested. “Different apparatus procedures and techniques are required for different dosage forms because of significant differences in formulation design and the physicochemical properties of the drugs”. Dissolution tests have been developed for various drug delivery systems including immediate release solid dosage forms several controlled -release solid dosage forms and many novel and special dosage forms. Most of the tests with recommended apparatus and other specifications are now available as compendial standards in Pharmacopoeias and are used in pharmaceutical analysis and drug development for the various drug delivery systems. The dissolution test methods are also now designed to mimic. the general conditions encountered in the physiological environment of the GIT and thus hold promise for the establishment of in vitro-in vivo correlation IVIVC for many more pharmaceutical products. However some dosage forms still require more method development and refinement before standardized dissolution test methods can be recommended. Introduction: “Dissolution is the process by which a solid solute enters in a solution”. In the pharmaceutical industry it may be defined “as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interfacetemperature and solvent composition”. Dissolution is considered one of the most important quality control tests performed on pharmaceutical dosages.forms and is now developing into a tool for predicting bioavailability and in some cases replacing clinical studies to determine bioequivalence. Dissolution behaviour of drugs has a significant effect on their pharmacological activity.

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In fact a direct relationship between in vitro dissolution rate of many drugs and their bioavailability has been demonstrated and is generally referred to as in vitro-in vivo correlation IVIVC. In spite of IVIVC dissolution is not really a predictor of therapeutic efficiency. Rather it is a qualitative and quantitative tool which can provide valuable information about biological availability of a drug as well as batch-to-batch consistency of products. Dissolution tests are therefore used to confirm compliance with compendial specifications and are needed as part of a product license application. Additionally they are used during product development and stability testing as part of the specifications for the product. However no universal dissolution test has been designed that gives the same in vitro dissolution and in vivo bioavailability for different formulations and batches. Thus different compendial specifications have been developed for different formulations and dosage forms. Disintegration/dissolution process Solid dosage forms may or may not disintegrate when they interact with gastrointestinal fluid. following oral administration depending on their design. For disintegrating solid oral dosage forms:disintegration usually plays a vital role in the dissolution process since it determines to a large extent the area of contact between the solid and liquid. However it is well known that considerable dissolution of the drug can take place before complete disintegration of the dosage form A phenomenon which depends largely on the mechanism of disintegration and certain physicochemical properties of the drug such as its solubility. This could be important when considering the motility of the drug or dosage form and the release of the drug at specific sites in the gastrointestinal tract. Thus correlations have been established between disintegration times and dissolution rates for various pharmaceutical tablets It should be noted however that there is not always an automatic correlation between disintegration and dissolution especially for drugs with very low dissolution rates. For many drugs particularly those that are poorly soluble in the gastric fluid the rate-limiting step in the absorption process is the dissolution rate and a dissolution rate determination can therefore be a useful guide to comparative bioavailability. What is the definition of dissolution Dissolution is pharmaceutically defined as the rate of mass transfer from a solid surface into the dissolution medium or solvent under standardized conditions of liquid/solid interface temperature and solvent composition. It is a dynamic property that changes with time and explains the process by which a homogenous mixture of a solid or a liquid can be obtained in a solvent. It happens to

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chemically occur by the crystal break down into individual ions atoms or molecules and their transport into the solvent. Why dissolution testing is used for pharmaceuticals Dissolution testing is a critical preformulation solubility analysis research tool in the process of drug discovery that entails measuring the stability of the investigational product achieving uniformity in production lots and determining its in vivo availability. Thus this Dissolution testing is an essential requirement for the development establishment of in vitro dissolution and in vivo performance IVIVR registration and quality control of different dosage forms. Whereas Dissolution is defined as the process by which solid substance enters in solvent to yield a solution. Simply dissolution is a mass transfer from a solid surface to liquid phase. It clearly states that dissolution is a dynamic property. Why Dissolution Clearly depicts the importance of dissolution in pharmaceutical Quality control QC Research and Development RD and for Regulatory authorization. In Vitro dissolution testing is used in QC to assess batch to batch consistency and detect deviations of manufacturing to identify critical manufacturing variables like Binder effects Mixing effects Granulation Procedure Coating Parameters to assess Excipients role in different dosage forms and to study the non-traditional production effects associated with NDDS. In RD it is used to assess the in vivo performance of drug product. It is used as a waiver for BA-BE studies for BCS class I drugs. It is used as the evidenced document for SUPAC and ICH guidelines. When is dissolution important Figure 2 depicts two important stages of drug release and drug absorption. Drug release is important especially for Delayed and Modified release dosage forms where as drug absorption is important for immediate release dosage forms. The importance of dissolution can be determined if the IDR is known. 2 Intrinsic dissolution rate IDR is defined as “the rate at which a pure substance dissolves from constant surface area under constant temperature PH Agitation and Ionic Strength of dissolution medium. When the drug is released from dosage form if the IDR value of a drug candidate is greater than or equal to 1.0 mg/min/cm 2 it infers that drug dissolution will not be the rate limiting/determining step to absorption if the IDR value is less than or equal to 0.1 mg/min/cm 2 it infers that drug dissolution will be the rate limiting step to absorption. While the intermediate value of IDR represents the “may be” version of rate limiting step. Therefore dissolution studies are particularly important for poorly soluble drugs like BCS class II IV drug candidates where their absorption is typically dissolution rate-limited.

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OFFICIAL DISSOLUTION APPARATUS USP 30 classification 1. Rotating Basket Ph.Eur./BP/JP 2. Paddle Ph.Eur./BP/JP 3. Reciprocating Cylinder Ph.Eur. 4. Flow Through Cell Ph.Eur./BP/JP 5. Paddle Over Disk Ph.Eur. 6. Rotating Cylinder Ph.Eur. 7. Reciprocating Holder Apparatus 1 – Basket: Useful for • capsules • beads • delayed release / enteric coated dosage forms • floating dosage forms • surfactants in media Standard volume • 900/1000 ml • 1 2 4 liter vessels

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Apparatus 2 – Paddle

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Useful for • tablets • capsules • beads • delayed release / enteric coated dosage forms Standard volume • 900/1000 ml Method of first choice Advantages • easy to use • robust • can be easily adapted to apparatus 5 • long experience • pH change possible • can be easily automated which is important for routine investigations delayed release / enteric coated dosage forms can be easily adapted pH change possible can be easily automated which is important for routine investigations

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Apparatus 3 – Reciprocating cylinder Useful for • tablets • beads • controlled release formulations Standard volume • 200-250 ml per station ing cylinder controlled release formulations 250 ml per station

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Dissolution Testing of Various Dosage forms: The dissolution testing of various dosa SuspensionTopical and Transdermal Product Controle Release product forms for oral cavity including Chewable tablets Gums Suppositories Semi solid Dosage forms Dissolution Testing of Immediate Release IR Dosage forms “An immediate release dosage form is designed to deliver the drug rapidly into systemic circulation. Therefore the dissolution may be the rate limiting step for its absorption. Generally dissolution of IR dosage forms are been Paddle Reciprocating Cylinder and Flow and II apparatuses are used. Basket apparatus. EP uses Paddle Basket and Flow through apparatuses for solid dosage forms of tablets capsules The choice of apparatus is based on the knowledge regarding the formulation design dosage form performance. Test is carried out at temperature In general when Basket apparatus is used of the basket is used. Other mesh sizes may also be used if supported by necessary data documentation. It is generally used for capsules and floating type of dosage forms or to those which tend to disintegrate used to prevent the floating of capsule. Paddle apparatus is generally used for tablets. Operating speed of 50 is used in general. Numerous monographs are available evidencing the use of Basket a Testing of Various Dosage forms: he dissolution testing of various dosage forms like Immediate release SuspensionTopical and Transdermal Product Controle Release product ity including Chewable tablets Buccal/sublingual tablets Chewing ries Semi solid Dosage forms Soft gelatin Capsules and Aerosols. Dissolution Testing of Immediate Release IR Dosage forms USP An immediate release dosage form is designed to deliver the drug rapidly into systemic circulation. Therefore the dissolution may be the rate limiting step for its absorption. Generally dissolution of IR dosage forms are been conducted using apparatuses o Paddle Reciprocating Cylinder and Flow-through cell respectively. Most commonly II apparatuses are used. USP 1 Basket USP 2 Paddle and IP 1 Paddle and IP 2 EP uses Paddle Basket and Flow through apparatuses for solid dosage forms of tablets capsules” The choice of apparatus is based on the knowledge regarding the formulation design dosage form performance. Test is carried out at temperature of 37+0.5 In general when Basket apparatus is used rotating speed of 100 rpm with 40 of the basket is used. Other mesh sizes may also be used if supported by necessary data documentation. It is generally used for capsules and floating type of dosage forms or to those which tend to disintegrate slowly. For floating type of dosage forms sinkers may be used to prevent the floating of capsule. Paddle apparatus is generally used for tablets. Operating speed of 50 is used in general. Numerous monographs are available evidencing the use of Basket and Paddle whilst the Testing of Various Dosage forms: ge forms like Immediate release Modified release SuspensionTopical and Transdermal Product Controle Release product Powders Dosage Buccal/sublingual tablets Chewing Soft gelatin Capsules and Aerosols. USP IP BP EP JP An immediate release dosage form is designed to deliver the drug rapidly into systemic circulation. Therefore the dissolution may be the rate limiting step for its absorption. apparatuses of Basket through cell respectively. Most commonly I 1 Basket USP 2 Paddle and IP 1 Paddle and IP 2 EP uses Paddle Basket and Flow through apparatuses for solid The choice of apparatus is based on the knowledge regarding the formulation design 0 C or 37-0.5 C rotating speed of 100 rpm with 40-mesh screen of the basket is used. Other mesh sizes may also be used if supported by necessary data documentation. It is generally used for capsules and floating type of dosage forms or to slowly. For floating type of dosage forms sinkers may be Paddle apparatus is generally used for tablets. Operating speed of 50 is used in general. nd Paddle whilst the

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use of Reciprocating cylinder and Flow through cell apparatus is limited only to research works to date. Vincopecetine and Theophylline had been evaluated using Reciprocating cylinder making use of a P H gradient method and Flow through cell apparatus for reporting in vitro profiling of albendazole/tetracyclin in 0.1N HCl. Samples are withdrawn according to specifications with tolerance of +2 or -2. Apparatus 3 Reciprocating cylinder is not accepted by JP. The test is conducted on the equipment which was pre calibrated with USP Salicylic acid and Prednisone Calibrator tablets According to USP.The dissolution medium used should be deaerated and may be water buffered aqueous solution of P H 4-8 and dilute acid of 0.001 N to 0.1 N HCl are used. The test time is 30-60 minutes and with a single point specification or as specified in individual monographs. Interpretation: The dissolution is done in three stages of S1 S2 and S3. In first stage S1 six units are taken and the amount of drug from each unit should not be less than Q+5 where Q is the amount of dissolved active ingredient specified in individual monograph. Failure of first stage compensates to conductance of second stage S2 where additional 6 units are tested and the average of 12 units in two stages should be equal to or greater than Q and no unit should be less than Q-15. Failure of stage 2 leads to conductance of stage S3 where additional 12 units are tested and the average of total 24 units of three stages S1 S2 and S3 should be greater than or equal to Q and no two units should be less than Q-15 and none should be less than Q-25. Dissolution Testing of Delayed Release Dosage Forms USP IPDissolution testing for Prolonged dosage forms BP JP EP According to CDER guidelines Delayed Release Dosage Forms are “the products that release the drugs at a time later than immediately after administration i.e. these drug products exhibit a long time in quantifiable plasma concentrations”. So the dissolution is done to show that they are intact in stomach pH and release the drug only in intestinal region. Test is carried out at temperature of 37+0.5 0 C or 37-0.5. Apparatusses Basket Paddle Reciprocating Cylinder and Flow-through cell are used for dissolution testing of delayed release dosage forms By USP BP IP and EP uses Paddle Basket and Flow through apparatuses whilst JP recommends only Flow through cell apparatus for dissolution testing 17 . The dissolution is done in two stages one in Acid stage to show the intactness of dosage form and in Buffer stage to evidence the drug release in specific region. Two methods are used for testing which include

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Method A: The test is carried out by placing the dosage form in 750 ml of 0.1N HCl. The sample was withdrawn after two hours and analyzed. Immediately within 5 minutes 250ml of phosphate buffer is added and contents are mixed thoroughly and final P H of buffer is adjusted to 6.8+0.05 or 6.8-0.05. The test is run for another 45 minutes or as specified in individual monographs and the sample is analyzed. Method B: Here the test is initially carried out by placing the dosage form in 1000ml of 0.01 N HCl and sample is analyzed after two hours and the medium is discarded and 1000ml of 6.8+0.05 or 6.8-0.05 buffer is added and the test is run for 45 minutes more or as specified in individual monographs. apparatuses Basket Paddle Flow throgh cell make use of method A B while Reciprocating cylinder make use of method B with 300ml of dissolution medium. The dissolution of delayed release dosage forms is said to be three three-tiered approach since the dissolution is done in three stages of two buffers A1 A2 A3 B1 B2 B3 Dissolution Testing of Extended Release Dosage Forms USP IP JP BP EPDissolution testing for Prolonged dosage forms These include sustained release or controlled release dosage forms which reduces the frequency of dosing compared to conventional dosage forms. The dissolution is done to study the effect of pH on release profile of dosage form when it passes through GIT. Test is carried out at temperature of 37+0.5 0 C or 37-0.5 Apparatuses 1 Basket or apparatus 2 Paddle are used at higher rotational frequencies.According to USP IP BP JP EP Apparatus 3Reciprocating cylinder is used for testing bead type formulations. According to USP IP BP Apparatus 4 Flow cell is used for dosage forms containing limited solubility of API. According to USP IP BP JP EP Apparatuses 5 6 Paddle over disk Cylinder are used for evaluating Transdermal dosage forms. According to USP Apparatus 7 Reciprocating disk is used for evaluating Transdermal as well as non- disintegrating oral dosage forms. According to USP The test is done over a wide pHrange of 0.1N HCl to 7.5pH over 22 hours. According to USP. Physiological pH of 0.8-2 stomach pH 5-6.5 jejunummid intestine pH 6-7.5 ileum are used according to EP 17 . Three test time points will be specified in monographs. Early time point of 1-2 hours is established to prove that there i3s no probability of dose dumping of drug. Intermediate time point is established to study the in vitro release profile of drug and final time point is chosen to show the complete release of drug.

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Dissolution Testing of Transdermal Delivery Systems : USP apparatus 5 6 and 7Paddle over disk Cylinder and Reciprocating holder are used for testing at temperature of 32+0.5C or 32-0.5C. Generally three time points may be specified in hours and the samples should be withdrawn with +2 or -2 tolerance intervals. —Use the paddle and vessel assembly from Apparatus 5 Paddle over disk or 2 as described in Dissolution with the addition of a stainless steel disk assembly 1 designed for holding the transdermal system at the bottom of the vessel. The temperature should be maintained at 32 ± 0.5 °C. During the test maintain a distance of 25 ± 2 mm between the paddle blade and the surface of the disk assembly. Procedure:Place the stated volume of the Dissolution Medium in the vessel assemble the apparatus without the disk assembly and equilibrate the medium to 32 ± 0.5 °C. Apply the transdermal system to the disk assembly ensuring that the release surface of the system is as flat as possible. The system may be attached to the disk by applying a suitable adhesive 3 to the disk assembly. Dry for 1 min. Press the system release surface side up onto the adhesive-coated side of the disk assembly. If a membrane 4 is used to support the system it should be applied in such a way that no air bubbles occur between the membrane and the release surface. Place the disk assembly flat at the bottom of the vessel with the release surface facing up and parallel to the edge of the paddle blade and surface of the Dissolution Medium. The bottom edge of the paddle should be 25 ± 2 mm from the surface of the disk assembly. Immediately start operation of the apparatus at the rate specified in the monograph. At each sampling time interval withdraw a specimen from a zone midway between the surface of the Dissolution Medium and the top of the blade not less than 1 cm from the vessel wall. Perform the analysis on each sampled aliquot as directed in the individual monograph correcting for any volume losses In Vitro Drug Release study of topical Drug Using the VDC: A VDCvertical diffusion cell system is used to determine in vitro release of semisolid cream ointment and gel preparations. Typically 200–400 mg of a cream ointment or gel is spread evenly over a suitable synthetic inert support membrane. The mem brane with its application side up is placed in a vertical diffusion cell typically of 15-mm diameter orifice e.g. a Franz cell. The release rate experiment is carried out at 32 + 1 oC except in the case of vaginal creams for which the temperature should be 37 + 1 oC. Sampling generally is performed over 4–5 hours and the volume sampled is replaced with fresh receptor medium. To achieve sink conditions the receptor medium must have a high capacity to dissolve or carry away the drug and the receptor media should not exceed 10 of Cs drug solubility in the releasing matrix at the end of the test.

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Dissolution Testing of Powders: Not accepted by IP BP EP JP USP As such no official method was developed for dissolution testing of powders. The preliminary method used was the determination of IDR where the powders are pressed like a tablet to mimic constant surface area. Literature has been reported with use of USP apparatus 2 and 4 for dissolution testing of finely divided particles. To counteract the effect of dispersal of powders a modified basket method was developed where the basket was dipped into the molten wax to seal the bottom so that there will be long term contact of drug with Excipients. Dissolution Testing of Dosage forms for the Oral Cavity : Development of dissolution method for these dosage forms possess several challenges due to short residence time of dosage form in the mouth and limited volume of dissolution medium for dissolving the dosage form. • Chewable Tablets: Not accepted by IP BP EP JP USP insisted the use of apparatus 2 for dissolution excepting Ampicillin where apparatus 1 is recommended and Carbamazepine where apparatuses 2 3 are used. The design of apparatus should consists of a mechanical breakage of tablet prior to dissolution. • Buccal/Sublingual Tablets Not accepted by IP BP EP JP Initially USP stated the use of disintegration apparatus for ergotamine category sublingual products. Later modified USP 3 apparatus with 20 strokes/min was used for Hydrocortisone mucoadhesive tablets to mimic the low dissolution volume of in vivo. Later another system Continuous Flow though Filtration Cell with dip tube for filtration. 10 ml of fluid is pumped to give a short residence time of 8 minutes. • Chewing Gums Not accepted by IP BP JP USP has not recommended any apparatus for dissolution testing of Chewing gums. But EP has emphasized on the use of 3-piston apparatus that chews the gum at a rate of 60cycles/min in dissolution medium of P H 6.0 at 37 C. Still controversies regarding this issue are existing and urges for development of an appropriate apparatus. Dissolution Testing of Soft Gelatin Capsules: Not accepted by IP BP EP JP USP has recommended the use of apparatuses 1 and 2. But since there had been serious disadvantages related attempts had been made in literature to develop new methods for lipid-filled soft gelatin capsules. Dissolution Testing of Aerosols: Not accepted by IP EP JP USP Literature has reported the use of designed flow through cell apparatus for dissolution testing of aerosols. The method uses the collection of of aerosol particles on to a pre filter which are obtained through impaction. The particles are made to flow through by using HPLC pump at 0.7 ml/min flow rate and the fraction of drug dissolved was collected on the

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upper filter and analyzed. Different mediums were reported like Simulated Lung Fluid SLF Modified SLF with D-Phosphatidyl Choline DPPC and Serum Ultra filtrate Simulant SUF. Dissolution Testing of Suppositories and other Semisolids USP EP Dissolution testing of Semisolid dosage forms for vaginal pessaries percutaneous application gels creams ointments patches ophthalmic gel cream ointment rectal suppository gel ointment cream may present problems like deformation change of solid state to oily state softening during the test. Therefore a modified flow-through cell with double chamber modified basket or paddle with a sinker and wired screen may be suitable for lipophilic suppositories while conventional paddle flow through basket may be used for hydrophilic suppositories. Dissolution Testing of suspenson: "Apparatus 2 Paddle using an aqueous dissolution medium is generally recommended for dissolution testing of oral suspensions. Product preparation should follow a standardized procedure shaking or mixing sample weight and volume should reflect a typical dose of the product. Method parameters such as sample introduction and agitation rate should be based on the viscosity and composition of the suspension matrix. Agitation rate is typically 25 rpm for less viscous suspensions and 50 or 75 rpm for high viscosity suspensions." Later in the same chapter: "In order to adequately characterize the release from the dosage form a drug release profile should be generated in which release dissolution values are determined as a function of time. This multi-point characterization has been in place for some time for modified release oral dosage forms as well as for slower dissolving IR products. Many of the special dosage forms discussed in this chapter incl. oral suspensions are complex in terms of composition and release machanism so a multi-point release test is required to characterize release of the drug product in general as well as to test batch- to-batch and shelf life consistencies." From my own experience consistent and repeatable introduction of constituted suspensions to the dissolution vessel is key to success. For our particular application a 10 mL syringe with sample canula attached was used to introduce the sample at paddle blade level.

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