Disolution best

Dissolution

Compiled by-Shamon Ahmad Gaur, Pawan Sidana and Ritika Gupta M.Pharma (Q.A) Chandigarh Group of Colleges,

Landra, Mohali( India) [email protected]

“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 interface,temperature 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.

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

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 (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.

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/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.

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

Apparatus 2 – Paddle

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

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 dosaSuspension,Topical 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 Flowand II apparatuses are used. (Basket apparatus). (EP uses Paddle, Basket and Flow through apparatuses for solid dosage forms of tablets, capsulesThe choice of apparatus is based on the knowledge regarding the formulation design, dosage form performance. Test is carried out at temperatureIn 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 disintegrateused 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 releaseSuspension,Topical 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 (USPAn 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 oPaddle, 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 40of 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, Suspension,Topical 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, 0C 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

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/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, IP(Dissolution 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 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)

Dissolution Testing of Extended Release Dosage Forms (USP, IP, JP, BP, EP(Dissolution 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 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 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 (jejunum){mid intestine}, 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 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.

Dissolution Testing of Transdermal Delivery Systems :

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.

—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 VDC(vertical 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.

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 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: (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

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.