Dissolution testing of various dosage forms
What is Dissolution???1
There is a crystal clear anomaly between solubility and dissolution.
Solubility is the maximum amount of solute accommodated by the solvent under standard conditions. It is a static property.
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.
Figure 1 clearly depicts the importance of dissolution in pharmaceutical Quality control (QC), Research and Development (R&D) 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 R&D 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.
Figure 1: Applications of In Vitro Dissolution Testing3
When is dissolution important???
Figure 2: Drug Transport and the Rate Limiting Step
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.1
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/cm2, 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/cm2 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.4
Dissolution Testing of Various Dosage forms:
An attempt is made here in to describe the dissolution testing of various dosage forms like Immediate release, Delayed release, Modified release, Powders, Dosage forms for oral cavity including Chewable tablets, Buccal/sublingual tablets, Chewing Gums, Suppositories & Semi solid Dosage forms, Transdermal Drug Delivery Systems, Soft gelatin Capsules and Aerosols.
Dissolution Testing of Immediate Release (IR) Dosage forms (USP, IP, BP, EP, JP) 2, 5, 6, 7, 8
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 of Basket, Paddle, Reciprocating Cylinder and Flow-through cell respectively. Most commonly I and II apparatuses are used. (USP 1 Basket, USP 2 Paddle and IP 1 Paddle and IP 2 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 of 37+0.5 0C or 37-0.5 C
In general when Basket apparatus is used, 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 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 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 PH gradient method and Flow through cell apparatus for reporting in vitro profiling of albendazole 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.
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%.
Table 1: Acceptance Criteria for Immediate Release Dosage Forms (IP, USP, JP, BP, EP)
Dissolution Testing of Delayed Release Dosage Forms (USP, IP(Dissolution testing for Prolonged dosage forms), BP, JP, EP)2, 5, 9
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 lag 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 0C 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
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 PH 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)
Table 2: Acceptance Criteria for Delayed Release Dosage Forms (USP, BP, IP2007, EP, JP)
Dissolution Testing of Extended Release Dosage Forms (USP, IP, JP, BP, EP(Dissolution testing for Prolonged dosage forms)) 2, 5
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 0C 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 3(Reciprocating 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 PH range of 0.1N HCl to 7.5 PH over 22 hours. (According to USP). Physiological pH of 0.8-2 (stomach); pH 5-6.5 (jejunum), pH 6-7.5 (ileum) are used according to EP17. Three test time points will be specified in monographs.
Early time point of 1-2 hours is established to prove that there is 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.
Table 3: Acceptance Criteria for Extended Release Dosage Forms (USP, BP, EP, JP, IP)
Dissolution Testing of Transdermal Delivery Systems 2, 5, 6, 10
USP apparatus 5, 6 and 7(Paddle 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.
Table 4: Acceptance Criteria for Transdermal Delivery Systems (USP)
Dissolution Testing of Powders (Not accepted by IP, BP, EP, JP, USP) 11, 12, 13, 14
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 2, 5, 6, 15
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 PH 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 5, 6, 19, 20(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 6, 16 (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 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) 2, 6 ,18, 19, 20
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.
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List of Abbreviations
API: Active Pharmaceutical Ingredient
BA-BE: Bioavailability and Bioequivalence
BCS: Biopharmaceutical Classification System
EP: European Pharmacopoeia
GIT: Gastrointestinal Tract
ICH: International Conference on Harmonization
IDR: Intrinsic Dissolution Rate
i.e. : That is
NDDS: Novel Drug Delivery Systems
NMT: Not More Than
QC: Quality Control
R&D: Research and Development
SUPAC: Scale Up and Post Approval Changes