International Journal of Drug Research and Technology

DISSOLUTION SPECIFICATIONS, DISSOLUTION PROFILING AND DISSOLUTION PROFILES COMPARISON METHODS

 

Int. J. Drug Res. Tech. 2012, Vol. 2 (4S), 297-305                 ISSN   2277 - 1506

International Journal of Drug Research and Technology

Available online at http://www.ijdrt.com/

Review Article

DISSOLUTION SPECIFICATIONS, DISSOLUTION PROFILING AND DISSOLUTION PROFILES COMPARISON METHODS

Meher Priya Sharma*, Saroj Jain and Neeraj

Department of Pharmaceutics, Hindu College of Pharmacy,

Sonepat-131001(Haryana), India

ABSTRACT

Drug dissolution testing plays an important role as a routine quality control test, for characterizing the quality of the product, for accepting product sameness under SUPAC (Scale-Up and Post-Approval Changes) related changes, in waiving bioequivalence requirements for lower strengths of a dosage form, and in supporting waivers for other bioequivalence requirements. The guidance of dissolution developed by regulating agencies provides recommendations on the development of dissolution test methodology, on how to set specifications for dissolution testing. As time is passing away, the in vitro dissolution testing is relied on to assure product performance, therefore one must design an appropriate dissolution test procedure which should be simple, economical method that can be utilized effectively in developing countries to assure acceptable drug product quality. The dissolution testing is enjoying a resurgence of interest on an academic as well as on industrial and regulatory levels. Provided the groundwork continues to be focused on the development of dissolution tests and testers that are both bio relevant and can be adapted to routine quality control, it is likely that dissolution testing will become even more powerful tool for the assurance of product quality, in its broadest sense in the years to come.

Keywords: Dissolution, Biopharmaceutical classification system, In-Vitro In-Vivo Correlation, Solubility, Permeability.


INTRODUCTION

Dissolution testing over the last quarter century has emerged as a highly valuable in vitro test to characterize drug product performance. For a useful dissolution test: it must be simple, reliable and reproducible and must be able to discriminate among different degrees of product performance. Dissolution test value is significantly enhanced when product performance is evaluated as a function of time (drug release profile with respect to time), which means that, when the dissolution profile is determined rather than a single point determination, which is a standard compendia for batch release. During the development of pharmaceutical product, dissolution testing is used as a tool to identify formulation factors that are influencing and may have a crucial effect on the bioavailability of the API. As soon as the composition and manufacturing process are defined, dissolution testing is used in quality control of scale-up and of production batches to ensure both batch-to-batch consistency and that; the dissolution profiles remain similar to those of pivotal clinical trial batches. Furthermore, dissolution testing can be used to support the bioavailability of a new pharmaceutical product, the bioequivalence of an essentially similar product or variations.8,10,11

In summary, dissolution testing is performed  

 In vitro dissolution characterization is encouraged for all product formulations investigated (including prototype formulations), particularly if in vivo absorption characteristics are being defined for the different product formulations.  Such efforts may enable the establishment of an in vitro-in vivo correlation. When an in vitro-in vivo correlation or association is available the in vitro test can serve not only as a quality control specification for the manufacturing process, but also as an indicator of how the product will perform in vivo.

Setting Dissolution Specifications

These specifications should be confirmed by comparison of dissolution performance of multisource pharmaceutical product and reference product from an acceptable bioequivalence study.

If the dissolution performance of multisource pharmaceutical product is substantially different from that of reference product and the in vivo data remain acceptable, a different dissolution specification for multisource pharmaceutical product may be set.

Once dissolution specifications are set, the pharmaceutical product should comply with those specifications throughout its shelf-life.

Testing should continue through three stages of testing (according to the USP) unless the product conforms at stage 1 or 2.

Setting dissolution specifications for multisource pharmaceutical products may be classified in three categories as described below.6,7

   I.     Pharmacopoeial Product Dissolution Test Available

In this instance quality control dissolution test should be the test described in the BP or USP. Use of any other pharmacopoeia should be justified and acceptable to the MCC.

It is recommended that a dissolution profile be generated by taking samples at 15-minute intervals, or less, using the specified pharmacopoeial method for test and reference products (12 units each).

Additional dissolution data may also be required when scientifically justified, e.g., when the pharmacopoeia does not specify a dissolution test for all APls in a combination product. If appropriate, the pharmacopoeial specification may be adopted. 6,7

II.     Pharmacopoeial Product Dissolution Test Not Available

If there is no pharmacopoeial method available, the FDA method for the reference listed product may be considered. Alternatively, a dissolution method developed according to the criteria below should be submitted.

Comparative dissolution testing, using test and reference products under a variety of test conditions, is recommended.

Criteria to be considered include:

In all cases, profiles should be generated as previously recommended. The medium, which exhibits optimum discrimination, should be selected. The method used should be justified and validated, for modified release products, as above. 6,7

III.     Special Cases

For poorly water soluble drug products (e.g. glyburide), dissolution testing at more than one time point, and preferably a dissolution profile, is recommended for quality control purposes. Alternatively, the use of USP apparatus 4 (Flow-Through Method) should be considered for development of dissolution specifications for such products.   If a monograph for a fixed-dose combination is not included in the USP or BP, the monographs for individual components should be used to set dissolution requirements for each.6,7

BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)                        

Biopharmaceutics Classification System (BCS) is a fundamental guideline for determining the conditions under which in-vitro in-vivo correlations are expected.4   It is also used as a tool for developing the in-vitro dissolution specification.5,19

The classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers: the Absorption number, the Dissolution number and the Dose number.4,5,19

The Absorption number is the ratio of the mean residence time to the absorption time.

The Dissolution number is a ratio of mean residence time to mean dissolution time.

The Dose number is the mass divided by an uptake volume of 250 ml and drug’s solubility.

The mean residence time here is the average of residence time in stomach, small intestine and the colon.

The fraction of dose absorbed then can be predicted based on these three parameters. For example, Absorption number 10 means that permeation across intestinal membrane is 10 times faster than the transit through small intestine indicating 100% drug absorbed.1 In the BCS, a drug is classified in one of four classes based solely on its solubility and intestinal permeability.19

Class I

HIGH solubility / HIGH permeability,

Class II

LOW solubility / HIGH permeability,

Class III

HIGH solubility / LOW permeability,

Class IV

LOW solubility / LOW permeability.

Class I drugs such as metoprolol exhibit a high Absorption number and a high Dissolution number.

The rate-limiting step to drug absorption is drug dissolution or gastric emptying rate if dissolution is very rapid.

Class II drugs such as phenytoin has a high Absorption number but a low Dissolution number.  In-vivo drug dissolution is then a rate-limiting step for absorption (except at very high Dose number). The absorption for Class II a drug is usually slower than Class I and occurs over a longer period of time. IVIVC is usually expected for Class I and Class II drugs.

For Class III drugs, permeability is the rate-controlling drug absorption. Furthermore, Class III drugs exhibit a high variability of rate and extent of drug absorbed. Since the dissolution is rapid, the variation is due to alteration of GI physiological properties and membrane permeation rather than dosage form factors.

Class IV drugs are low solubility and low permeability drugs. Drugs that fall in this class exhibit a lot of problems for effective oral administration.  Drug example for class III and IV is cimetidine and chlorothiazide, respectively. In general, a high soluble drug is characterized based on the largest dosage strength soluble in 250 ml or less of water over a pH range of 1-8. In addition, if the extent of drug absorption is greater than 90% given that the drug is stable in the gastrointestinal environment; it will be considered as a high permeable drug.5

Table 1 and 2 illustrate the BCS and the expected IVIVC for immediate and extended release formulations.4


  Table 1: Biopharmaceutics Drug Classification and Expected IVIVC for Immediate Release Drug     Products

Class

 Solubility

Permeability

 IVIVC

I

High

High

Correlation (if dissolution is rate limiting step)

II

Low

High

IVIVC expected

III

High

Low

Little or no IVIVC

IV

Low

Low

Little or no IVIVC

Table 2: Biopharmaceutics Drug Classification for Extended Release Drug Products

Class

Solubility

Permeability

IVIVC

IA

 

 

High & Site Independent

 

High & Site Independent

IVIVC

Level A expected

IB

 

 

High & Site Independent

 

Dependent on site & Narrow Absorption Window

IVIVC

Level C expected

IIa

 

 

Low & Site Independent

 

High & Site Independent

IVIVC

Level A expected

IIb

 

 

 

Low & Site Independent

Dependent on site & Narrow Absorption  Window

Little or no IVIVC

Va:

Acidic

Variable

Variable

Little or no IVIVC

Vb:

basic

 

Variable

Variable

IVIVC

Level A expected

 


DISSOLUTION PROFILS GENERATED CONSIDERING FOLLOWING VARIABLES

Medium

Physical and chemical data for the drug substance and dosage unit need to be determined before selecting the dissolution medium.  Two key properties of the drug are the solubility and solution state stability of the drug, as a function of pH values.  When selecting the composition of the medium, the influence of buffer, pH value, and surfactants on the solubility and stability of the drug need to be evaluated.

Generally, when developing dissolution procedure, one goal is to have sink conditions, defined as the volume of medium at least three times that required in order to form a saturated solution of drug substance. When sink conditions are present, it is more likely that dissolution results will reflect the properties of the dosage form.  A medium that fails to provide sink conditions may be acceptable if it is shown to be more discriminating or otherwise appropriately justified.

Purified water is often used as dissolution medium, but is not ideal for several reasons.  First, the quality of the water can vary depending on the source of water, and the pH value of the water is not controlled.  Second, the pH value can vary from day to day and can also change during the run, depending on the active substance and excipients. Despite these limitations, water is inexpensive, readily available, easily disposed of, ecologically acceptable and suitable for products with a release rate independent of pH value of the medium.

The dissolution characteristics of an oral formulation should be evaluated in the physiologic pH range of 1.2 to 6.8 (1.2 to 7.5 for modified – release formulations).  During method development, it may be useful to measure the pH before and after a run to discover whether the pH changes during the test.  Selection of the most appropriate conditions for routine testing is then based on discriminatory capability, ruggedness, stability of analyte in the test medium, and relevance to in vivo performance, where possible.

Typical media for dissolution may include the following (not listed in order of preference)

1. Dilute hydrochloric acid

2. Buffers in the physiological pH range of 1.2 to 7.5

3. Water

4. Surfactants (with or without acids or buffers) such as polysorbate 80, sodium lauryl sulphate

5. Bile salts

Note: the molarity of the buffer & acids used can influence the solubility effect, and this factor may be evaluated.

Volume

Normally for basket and paddle apparatus, the volume of the dissolution medium is 500 ml to 1000 ml, with 900 ml as the most common volume.  The volume can be raised 2 and 3 using larger vessels and depending on the concentration and conditions of drug; justification for this procedure is explained.2

Deaeration

The significance of deaeration of the medium should be determined, because air bubbles can interfere with the test results acting as a barrier to dissolution if present on the dosage unit in basket mesh.  Further, bubbles can cause particles to cling to the apparatus and vessel walls.  On the other hand, bubbles on the dosage unit may increase buoyancy, leading to an increase in the dissolution rate, or may decrease the available surface area, leading to decrease in the dissolution rate.2

Method - Typical Steps include

Heating the medium

Filtering

Drawing a vacuum for short period

Note 1. Media containing surfactants are not usually deaerated because the process results in excessive foaming.

2. To determine whether deaeration of medium is necessary, results from dissolution samples run in non–deaerated medium and deaerated medium should be compared.

Enzymes

The use of enzymes in the dissolution medium is permitted as accordance with dissolution when dissolution failures occur as a result of cross – linking with gelatin capsules or gelatin – coated products.2

Agitation

For immediate release capsule or tablet formulations, Apparatus I (baskets) at 100 rpm or Apparatus II (paddles) at 50 or 75 rpm are most commonly used.  Other agitation speeds and apparatus are acceptable with appropriate justification.

Note → Rate outside 25 to 150 rpm are usually inappropriate because of the inconsistency of hydrodynamics below 25 rpm and because of turbulence above 150 rpm.

For dosage forms that exhibit coning (mounding) under the paddle to 50 rpm, the coning can be reduced by increasing the paddle speed to 75 rpm, thus reducing the artifact and improving the data.

If justified, 100 rpm may be used, especially for extended – release products.

Decreasing or increasing the apparatus rotation speed may be justified if the profiles better reflect in vivo performance and/ or the method results in better discrimination without adversely affecting method reproducibility.2

Time Points:

A sufficient number of time points should be selected to adequately characterize the ascending and plateau phases of the dissolution curve.

According to the BCS referred to in several FDA guidances, highly soluble, highly permeable drug formulated with rapidly dissolving products need not be subjected to a profile comparison if they can be shown to release 85% or more of the active drug substance within 15 minutes.  For these products a one-point test will suffice. However, most products do not fall into this category.  Dissolution profiles of immediate – release products typically show a gradual increase reaching 85% to 100% at about 30 to 45 minutes.  Thus, dissolution time points in the range of 15,20,30,45 and 60 minutes are usual for most immediate release products. For slower – dissolving products, time points later than 60 minutes may be useful.  Dissolution test times for compendial tests are usually established on the basis of an evaluation of the dissolution profile data. So called infinity points can be useful during development studies.  To obtain an infinity point, the paddle or basket speed is increased at the end of the run for a sustained period (typically 15 to 60 minutes), after which addition sample is taken.2

Sampling:

Manual

 Manual sampling uses plastic or glass syringes, a stainless steel cannula that is usually curved to allow for vessel sampling, a filter, and/or a filter holder. 

Auto sampling

Auto sampling is a useful alternative to manual sampling especially if the test includes several time points.  However, because regulatory labs may perform the dissolution test using manual sampling, auto sampling requires validation with manual sampling.

Filters

Filtration of the dissolution samples is usually necessary to prevent undissolved drug particles from entering the sample and further dissolving.  Also, filtration removes the excipients that may otherwise cause high background.2

Prewetting of the filter with the medium may be necessary.

Filter can be in-time or at the end of the sampling probe.  The pore size can range from 0.45 to 70 ᴜm.

The usual types of filters are

1. Depth

2. Disk

3. Flow through

COMPARISON OF DISSOLUTION PROFILES

Model independent method

Dissolution of test and reference products should be conducted in each of the following three media:

1.      Acidic media such as 0.1 N HCL

2.      pH 4.5 Buffer

3.      pH 6.8 Buffer

Two scenarios for comparing the profiles obtained from multipoint dissolution are operative

1.      If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered similar (no calculation required). If not, see the next point.

2.      Calculate the f2 value. If f2 ≥ 50, the profiles are normally regarded similar such that further in vivo studies are not necessary. Note that only one measurement should be considered after 85% dissolution of both products has occurred and excluding point zero.

The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared errors, and is a measurement of the similarity in the percentage (%) dissolution between two curves.3,9

 f2 = 50.Log {[1 + (1/n)∑ t=1ⁿ(Rt  - Tt)²]¯°·.100

Where, n is the number of time points, R, is the dissolution value of the reference batch at time t and T is the dissolution value of the test batch at time t.

A specific procedure to determine difference and similarity factor is as follows:

a.         Determine the dissolution profile of two products, i.e.  of the test and  reference products (using 12 units each).

b.        For f2 calculations a minimum of three time points (excluding point zero) must be used, and only one measurement included after 85 % dissolution of both products has occurred.

c.         For curves to be considered similar, f2 values should be close to 100.  Generally, f2 values greater than 50 (50 to 100) ensure sameness or equivalence of the two curves and, thus, of the performance of the test and reference products

Model dependent method

The kinetic models used were a zero order equation, First order equation, Higuchi’s model and korsmeyersPeppas model.13,14

1.    Zero order kinetics – A zero order release would be predicted by the following equation                               

At = Aₒ - Kₒ t

Where,

At = Drug release at time t

Aₒ = initial drug concentration

Kₒ = zero – order rate constant (mg/ml hr)

When data is plotted as cumulative percent drug release versus time, if the plot is linear then the data obeys zero order release kinetics, with a slope equal to Kₒ.

2.    First order kinetics – A First – order release would be predicted by the following equation

Log C = Log Cₒ - Kt/2.303

Where,

C = concentration of drug remaining at time t

Cₒ = initial concentration of drug

K = first order rate constant ( 1/ hr)

When the data is plotted as log cumulative percent drug remaining versus time yields a straight line, indicate that the release follows first order kinetics. The constant ‘K’ can be obtained by multiplying 2.303 with the slope values.

3.    Higuchi’s model – Drug released from the matrix devices by diffusion has been described by following Higuchi’s classical diffusion equation

Q = [( 2AεCs)]Cst^1/2

Where,

Q = amount of the drug released at time t

D = Diffusion coefficient of the drug in the matrix

A = total amount of drug in the volume of matrix

Cs = the solubility of the drug in the diffusion medium

ε = porosity of the matrix

τ = tortuosity

t = time (hrs) at which Q amount of the drug is released  

Equation becomes:

              Q = K

When the data is plotted according to the equation i.e., cumulative drug release versus square root of time, yields a straight line, indicating that the drug was released by diffusion mechanism. The slope is equal to K.

4.    Korsmeyer and peppas model – The release rates from controlled release polymeric matrix can be described by the equation proposed by korsmeyers et al .

Q = K t^n

Where,

Q = is the percentage of drug release t

K = is a kinetic constant incorporating structural and geometric characteristics of the tablets an ‘n’ is the diffusional exponent indicative of the release mechanism for fickian release, n = 0.45 while for anomalous (Non-fickian ) transport, n ranges between 0.45 and 0.89 and for zero order release , n = 0.89.


Table 3: Mathematical Models used to describe Drug Release Kinetics from various Matrices18

Kinetic Model

Mathematical Relation

Systems that follow the Model

First Order

In Qt = In Qₒ + Kt

(release proportional to amount of drug release)

Water soluble drugs in porous matrix

Zero Order

ft = Kₒt

(drug release independent of drug concentration)

Osmotic systems, transdermal systems

Higuchi’s square root of time equation

ft = KHt^1/2

(release proportional to square root of time)

Diffusion matrix formulations

Weibull

m = 1 – e[-(t-Ti)^b/a]

Erodible matrix formulations

Hixon-crowell’s cube-root equation

Wₒ^1/3 –Wt^1/3 = Ks t

Erodible matrix formulations

Korsmeyers-Peppa’s power law equation

Mt/M ͚ =Kt^n

Swellable polymeric devices 

Peppas-Sahlin

Mt/M ͚ =Kt^m + Kt^2m

Swellable polymeric devices 

Baker-Lonsdale

3/2 [1- (1- Mt/M ͚)^2/3]- Mt/M ͚ = Kt

Microcapsules or microspheres

Where,

 a = scale parameter

 b = surface parameter

ft =fraction of dose released

K, KH, Kₒ, Ks = release rate constants characteristic to respective models

m and n = release exponents

Mt = amount released at time t

M ͚ = amount released at infinite time

Qₒ = drug amounts remaining to be released at zero hour

Qt = drug amounts remaining to be released at time t

Ti = lag time before the onset of dissolution

Wₒ = initial amount of drug present in the matrix

Wt = amount of drug released at time t


CONCLUSION

Comparing the In-Vitro Dissolution Profiles of a Tablet, Powder or Capsule provides the formulator with the critical information necessary to screen formulations during Product Development, Evaluate Stability and Optimize Dosage forms. The Quantitative analysis of the values obtained in Dissolution tests is easier when Mathematical formulas that express the Dissolution results as a function of some of dosage form characteristics is very effective.

REFERANCES

1.     International Journal of Generic Drugs, ISSN 0793 7776.

2.     (2007), “United States Pharmacopoeia”, 579-583.

3.     VP, Shah; Y, Tsong; P, Sathe and JP, Liu (1998), Pharm. Res., 15, 889.

4.      Young, D;  Devane, JG and Butler, J (1997), “In Vitro-In Vivo Correlations”, New York, Plenum press.

5.     Amidon, GL; Robinson, JR and Williams, RL (1997) “Scientific Foundations for Regulating Drug Product Quality”, American Association of Pharmaceutical Scientists, Alexandria, Virginia, AAPS Press.

6.     Guidance for Industry (1997), “Dissolution Testing of Immediate Release Solid Oral Dosage Form”, August 1997.

7.      Guidance for Industry (1997), “Extended Release Solid Oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations.

8.     Guidance for Industry (2000), “Waiver of In-Vivo Bioavailability and Bioequivalence Studies for Immediate- Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER).

9.      Moore, JW and Flanner, HH (1996), “Mathematical Comparison of Dissolution Profiles”, Pharm. Technol., 20 (6), 64-74.

10. Guidance for Industry (1997), “Dissolution Testing of Immediate Release Solid Oral Dosage Forms, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER).

11.  Guidance for Industry (1997), “Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro / ln Vivo Correlations”, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER).

12.  (2002), “CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence”, The European Agency for the Evaluation of Medicinal Products CPMPIEWPIQWPI1401198.

13.  (1995), “FIP Guidelines for Dissolution Testing of Solid Oral Products”, Joint report of the Section for Official Laboratories and Medicines Control Services and the Section of Industrial Pharmacists of the FIP.

14. (1997), “FIP Guidelines for Dissolution Testing of Solid Oral Products”, Joint report of the Section for Official Laboratories and Medicines Control Services and the Section of Industrial Pharmacists of the FIP.

15. Amidon, GL; Lennernas, H; Shah, VP and Crison, JR(1995), “A theoretical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability”, Pharm. Res.,12,413-420.

16.  HHSIFDA Guidance for Industry (2000), “Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system.

17. Yu, LX; Amidon, GL; Polli, JE et al. (2002), “Biopharmaceutics Classification System: The scientific basis for biowaiver extensions”, Pharrn. Res., 19,921-925.

18. DM, Brahmanker, Sunil B. Jaiswal (2009), “Biopharmaceutics and Pharmacokinetics a Treatise”, Second Edition, 432.

19.  Amidon, GL;  Lennernas, H; Shah, VP and Crison, JR (1995), “A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailabilty”,  Pharmaceutical Research, 12(3), 413-419.