Dissolution Method Development and IVIVC Explained

Dissolution Method Development: What the Test Must Achieve

Drug absorption from a solid dosage form depends on release of the drug substance from the product, its dissolution under physiological conditions and its permeability across the gastrointestinal tract. Because the first two steps are critical, FDA's immediate-release dissolution guidance says in vitro dissolution may be relevant to predicting in vivo performance. It names three uses: assessing lot-to-lot quality, guiding development of new formulations and ensuring quality after changes in formulation, process, site or scale. Each use asks the method to do something different, so the purpose comes before the apparatus.

The Biopharmaceutics Classification System therefore predicts where the development effort should go. FDA's 2018 guidance calls a product highly soluble if its highest strength dissolves in 250 mL or less of aqueous media. The test range is pH 1 to 6.8 at 37 ± 1 °C. Our guide to the FDA, ICH and USP regulatory pathway shows where dissolution data enter a filing.

With the purpose set, the next decision is the physical set-up of the test.

Apparatus, Medium and Agitation: Building the Method

Apparatus, medium and agitation are the three levers that set what a dissolution test can detect. FDA's guidance says the basket and paddle methods are simple, robust, well standardised and used worldwide, so USP Apparatus 1 and 2 should be used unless shown to be unsatisfactory. The reciprocating cylinder (Apparatus 3) and flow-through cell (Apparatus 4) may be considered if needed, on the basis of proven superiority for a particular product. Medium and agitation then follow from the physicochemistry of the drug substance.

FDA's extended-release guidance adds that an aqueous medium preferably not above pH 6.8 should be the initial medium for developing an IVIVC. For poorly soluble drugs it says a surfactant such as 1 percent sodium lauryl sulfate may be appropriate. It asks for profiles of at least 12 units per lot, with a coefficient of variation for the mean profile of a single batch below 10 percent. FDA's 2018 guidance points to USP General Chapter <711> Dissolution for apparatus information and the number of units to test.

• Dissolved air — FDA notes that certain products are sensitive to dissolved air in the medium and need deaeration.
• Floating capsules — capsules tend to float with the paddle method, so FDA recommends a few turns of a wire helix around the capsule.
• Pellicle formation — gelatin capsule products may need pepsin in gastric fluid or pancreatin in intestinal fluid to dissolve a pellicle if one forms. Our guides to gelatin and HPMC capsule shells and softgel capsule manufacturing cover the shell side.

Conditions only matter if the method can tell formulations apart, which is the test of a discriminating method.

Discriminatory Dissolution Methods: Detecting the Changes That Matter

A discriminating method responds to formulation and process differences that could change performance. FDA's immediate-release guidance prefers a more discriminative method from a quality assurance viewpoint, because the test will signal changes in product quality before in vivo performance is affected. The same guidance observes that the in vitro test is often more sensitive and discriminating than the in vivo test. Building that sensitivity takes a deliberate screening step, not a default set of conditions.

1. Characterise the drug substance — FDA says the method should be developed from the pH solubility profile and pKa, and permeability or octanol-water partition data may help.
2. Choose starting conditions — begin with USP Apparatus 1 or 2 and a medium that follows the physicochemistry.
3. Screen several methods early — FDA's extended-release guidance says dissolution testing can use several methods during formulation screening.
4. Challenge the method with deliberate variants — FDA's mapping approach tests products with the fastest and slowest dissolution, called side batches.
5. Fix the conditions — once a discriminating system exists, the same conditions apply to all formulations tested in the biostudy.
6. Validate the method — follow the validation steps in the section below.

The 2018 guidance also creates an exception. For eligible highly soluble immediate-release products it describes a standard method and says the standards remove any requirement to show discriminatory ability during development. Once the method discriminates, or qualifies for the standard route, the specification can be set around it.

Setting Dissolution Specifications: Single-Point, Two-Point and Profiles

FDA's immediate-release guidance describes three types of dissolution specification: single-point, two-point and profile comparison. Which one applies depends mainly on the solubility and dissolution rate of the drug product. The 2018 guidance adds a streamlined route for eligible highly soluble products. The table summarises the options.

The 2018 route applies only when the product meets every eligibility condition. FDA lists them, and its standard conditions are narrow.

• Dosage form — a solid immediate-release tablet or capsule meant to be swallowed, not an orally disintegrating or sublingual product.
• Solubility — the highest strength divided by 250 mL must not exceed the lowest solubility over pH 1 to 6.8 at 37 ± 1 °C. The drug must also be stable in the medium.
• Therapeutic index and onset — narrow therapeutic index products are excluded, and so are products with a claim of early or rapid onset.
• History and excipients — manufacturing and stability history must show the product meets the criterion, and excipient levels must suit their labelled function.
• Standard conditions — basket at 100 rpm or paddle at 50 rpm, 500 mL of 0.1 N HCl, no surfactant and 37 ± 0.5 °C.

A specification judges one batch against a limit, whereas comparing profiles judges whether a change altered performance.

Dissolution Profile Comparison and the f2 Similarity Factor

FDA's guidance uses dissolution profile comparison to accept product sameness after scale-up or postapproval changes and to support waivers for lower strengths. It describes a model-independent approach built on a difference factor, f1, and a similarity factor, f2. The f2 factor is a logarithmic reciprocal square root transformation of the sum of squared error between two curves. Values of f1 up to 15 and f2 above 50, within a range of 50 to 100, ensure sameness or equivalence of the two curves.

The formulas are f₁ = {[Σ|R_t − T_t|] / [ΣR_t]} × 100 and f₂ = 50 × log {[1 + (1/n) Σ(R_t − T_t)²]^−0.5 × 100}. Here n is the number of time points, R_t is the reference batch value and T_t is the test batch value at time t. FDA says the method suits profiles with three to four or more time points.

• Units and conditions — profile both products with 12 units each, under exactly the same conditions and with the same time points.
• Reference batch — use the most recently manufactured prechange product.
• Points after 85 percent — consider only one measurement after both products reach 85 percent dissolution.
• Variability limits — the coefficient of variation should not exceed 20 percent at early time points, such as 15 minutes, or 10 percent at the others.
• High variability — where within-batch variation exceeds 15 percent, FDA suggests a multivariate confidence region procedure instead.

For biowaivers, FDA says lower strengths with linear kinetics can be waived on dissolution profile comparison. They must be proportionately similar in composition under 21 CFR 320.22. Our guide to generic drug formulation development and bioequivalence shows how those waivers fit a development plan.

Profile comparison links two dissolution curves, and an IVIVC links dissolution to the body.

IVIVC: Levels A, B, C and Multiple C

An in vitro–in vivo correlation, or IVIVC, is a predictive model relating an in vitro property, such as dissolution, to an in vivo response, such as plasma concentration. FDA's extended-release IVIVC guidance defines four levels of correlation. Level A is the most informative and the one it recommends. The levels differ in how much of the in vivo curve they describe.

FDA describes the usual route to a Level A correlation in three steps. Develop formulations with different release rates, such as slow, medium and fast. Obtain in vitro dissolution and in vivo plasma profiles for each. Then estimate the in vivo absorption time course with a deconvolution technique such as Wagner-Nelson or numerical deconvolution.

• Number of formulations — two release rates define an IVIVC, and three or more are recommended, with release rates that differ adequately, for example by 10 percent dissolved.
• One system for all — the same dissolution system should be used for every formulation, and it should discriminate among them.
• Human data — FDA says human data should be supplied, in studies that have ranged from 6 to 36 subjects, with crossover designs preferred and the fasted state usual.
• Predictability — internal prediction error applies in all instances. External prediction error is appropriate when only two formulations are used, when internal results are inconclusive or when the drug has a narrow therapeutic index.
• Applications — once predictability is established, FDA outlines biowaivers for certain manufacturing changes without an in vivo bioequivalence study. Our guide to modified-release tablet technology covers the product design side.

A correlation is only as good as the method behind it, so the last technical question is how that method is validated and protected from common failures.

Validation, Calibration and Common Failure Points

FDA's Appendix A says validation of the dissolution apparatus and method should include four elements. These are the system suitability test using calibrators, deaeration if necessary, validation between manual and automated procedures, and validation of the determinative step, meaning the analytical method for dissolution samples. The determinative step should include all appropriate steps of analytical method validation. FDA also says apparatus suitability tests with a performance standard should be run at least twice a year and after any significant equipment change or movement.

FDA's 2018 guidance also cites its guidance on mechanical calibration of Apparatus 1 and 2 under current good manufacturing practice. Our guide to quality by design in pharmaceutical formulation development shows how a validated method fits a design-space approach. A method that survives these checks is ready for the development partner who will run it.

Working With a Pharmaceutical Formulation Consultant

Dissolution method development sits between physical pharmacy, analytical chemistry and regulatory strategy, and the method has to work on the real product. A pharmaceutical formulation consultant characterises the drug substance, screens methods and challenges them with side batches. Pharmaceutical product development services also cover specification writing, profile comparison and stability planning. Contract formulation CDMO support then carries the validated method and the product into a facility that can run both under GMP.

1. Define the purpose — release testing, formulation screening, change control or an IVIVC.
2. Characterise the drug substance — pH solubility profile, pKa, BCS class and permeability data.
3. Screen apparatus, media and agitation — compare methods at the formulation screening stage.
4. Challenge the method — run side batches and compare discrimination.
5. Set the specification — choose single-point, two-point or profile-based criteria.
6. Validate and transfer — complete validation, then transfer the method with the process.
7. Plan the stability and change-control programme — keep dissolution on the protocol and define the profile comparisons for future changes.

Our pharmaceutical and healthcare range shows where oral solid dosage forms sit among the other dosage forms. Our guide to choosing a pharmaceutical formulation consultant explains how to select a partner. The formulation side is covered in our guide to excipient selection for oral solid dosage forms. Global Formulation provides dissolution method development, specification support, profile comparison and scale-up for pharmaceutical developers. Product-specific release data and formulation ratios stay outside this guide by design.