Dissolution Testing: An overview

Rupinder K. Garcha and Ravi Muppa

Introduction
Dissolution is a test used throughout the life cycle of a pharmaceutical product to evaluate the rate of release of a drug substance
from the dosage form. Dissolution testing is routinely used for quality control purposes to test batch-to-batch consistency, stability
and detect manufacturing deviations of pharmaceutical products. Dissolution is not only for orally ingested products such as tablets
and capsules, it also applies to suspensions, beads, granules, topical formulations i.e. ointments, creams, gels, transdermal patches,
implants, powders for inhalation, suppositories etc.
However oral dosage forms remain one of the most flexible and effective treatments available to patients. Dissolution testing is a
requirement for all solid oral dosage forms and is used throughout the development life cycle for product release and stability testing. It is a
pivotal analytical test used for detecting physical changes in an active pharmaceutical ingredient and formulated product. At the early stages
of the drug development process, in-vitro dissolution testing underpins the optimisation of drug-release from a given formulation.
The exact dissolution technique employed is determined by the dosage form characteristics and the intended route of administration. For
solid dosage forms, the industry standard dissolution testing methodologies are the United States Pharmacopoeia (USP) Apparatus I (Basket)
and USP Apparatus 2 (Paddle). Immediate, modified and extended release are usually tested in standard dissolution baths with USP 2
paddles. Apart from the above-mentioned apparatus types, there are also other techniques available such as USP 3 (Reciprocating Cylinder),
USP 4 (Flow-through-Cell), USP 5 (Paddle-over-Disc), USP 6 (Rotating Cylinder) and USP 7 (Reciprocating Holder or Disc).
This paper focuses on solid dosage forms, different modes of drug release, critical parameters for development of dissolution method to
evaluate the release of drug form these dosage forms and how excipients impact the rate of dissolution.

Figure 1: Different types of dosage forms.

Critical parameters to control whilst selecting excipients: Important considerations to bear in mind
Excipients are an essential component of pharmaceutical formulations, and their physical properties can have a significant impact on the when developing a dissolution method:
performance and stability of the final drug product. Excipients can be incorporated in the formulation to assist in the dissolution process Active Pharmaceutical Ingredient (API) – This is the primary
of the drug, or specialized dosage forms can be formulated that improve dissolution rate through various mechanisms. Some key physical component of a drug that provides the therapeutic effect. For a dosage
properties of excipients that are important to consider during formulation development include: form to be efficacious, the API must be both extracted (dissolved in
Particle size and distribution – The particle size and distribution of excipients can impact the flow properties, mixing characteristics, and solution) and then absorbed into the systemic circulation to facilitate
dissolution rate of the final drug product. Smaller particle sizes can improve dissolution and bioavailability, while larger particle sizes can its transport to the active site. This process influences the overall
improve flow properties and ease of handling. bioavailability of the API. A simple diagrammatic representation is given
on the left (Figure 2).
Bulk density – The bulk density of excipients can impact the flow properties and compressibility of the final drug product. Higher bulk
density can improve flow properties, while lower bulk density can improve compressibility. Dosage form – The fundamental characteristics of the dosage
form type (capsule, tablet etc.), strength, excipients, release type
Porosity – The porosity of excipients can impact their ability to absorb or release moisture, which can impact the stability and performance
(immediate, sustained, delayed), stability data and surface coatings,
of the final drug product. Higher porosity can improve the flow properties and compressibility of excipients but can also increase their
should all be considered during the method development phase. A
moisture sensitivity.
well-developed dissolution method should allow discrimination of the
Hygroscopicity – Hygroscopicity refers to the ability of excipients to absorb and hold moisture from the environment. Excipients that are various product attributes.
highly hygroscopic can be more difficult to handle and can impact the stability of the final drug product.
Excipients – Excipients are the inactive ingredients used in the
Compressibility – The compressibility of excipients can impact the tablet hardness and disintegration of the final drug product. Excipients formulation of a drug product. API are not administered to patients
with higher compressibility can improve the compressibility and tablet hardness of the final product. on their own as single compounds but are formulated into carefully Figure 2: Dissolution of a solid oral dosage form.
designed dosage forms using different types of excipients which
Flowability – The flowability of excipients can impact the ease of handling and processing during formulation development. Excipients with
play different roles in the formulation. The functions of excipients
good flowability can improve the efficiency of the manufacturing process and reduce the risk of segregation or blending errors.
in dosage forms are related to all the different aspects of the final
Chemical stability – The chemical stability of excipients can impact the stability and efficacy of the final drug product. Excipients should be product including its manufacturability, the stability of the API, dose
chemically stable under the intended storage conditions to ensure the stability of the final product. uniformity, effective delivery of the API to the systemic circulation after
Compatibility with active pharmaceutical ingredient (API) – Excipients should be compatible with the API and not interact with it administration.
chemically or physically, as this can impact the stability, efficacy, and safety of the final drug product. Sink conditions – Sink conditions are defined as ‘the solution
concentration corresponding to typically 5-10 times the nominal
working concentration of the API in the dissolution medium’.
Critical parameters to consider when developing a dissolution method: Confirmation of achievement of sink is critical in establishing a suitable
dissolution method. If these are not able to be achieved (and hence
Dissolution testing is a critical step in drug development and quality control. Dissolution assesses the performance of drug products. To be the media reaches saturation point), the dissolution rate cannot
effective, the test should be: be consistently measured. It is important that when conducting
• Predictive dissolution testing, the only influences on the result should be the
• Comparative agitation rate and solubility of the product.
• Discriminatory Dissolution Media – This is the medium used in dissolution testing to
• Reproducible simulate the physiological conditions in the body. Different media can
When developing a dissolution method, it is important to take a logical, systematic approach to the process, and ensure that both the be used to mimic different parts of the gastrointestinal tract or other
scientific and regulatory principles are borne in mind. A robust dissolution method should be free of significant interferences (e.g. matrix biological environments.
effects due to excipients), give low variability (precision) and produce a good profile shape. The method should also be challenged to The initial focus when screening potential media is to start with
discriminate between batches of material with different quality attributes., but still maintain acceptable precision and robustness. those which are aqueous based, within the pH range of 1.2-6.8 at the Figure 3: Factors which may affect the in-vitro Dissolution.
recommended ionic strength (as per USP/EP). When assessing APIs (Adapted from Predictive in vitro dissolution tools: application
that display low solubilities in aqueous media throughout the pH range, during formulation development: Emmanuel Scheubel)
incorporation of a surfactant is advisable, although the levels used
should be as low as possible.
Apparatus – The apparatus used for dissolution testing can also influence the dissolution profile. Different types of apparatus are available,
such as the USP apparatus 1, 2, 3, 4, 5, 6 and 7 and the choice of apparatus depends on the specific drug product and the purpose of the
test.
Analytical Method – The analytical finish for the dissolution needs to be established. Where possible, in order to maintain simplicity and
efficiency (and assuming the presence of a suitable chromophore), a simple UV finish could be employed.
Acceptance criteria – These are the criteria established for the dissolution test results to determine if the drug product meets the
required quality standards. Acceptance criteria should be based on regulatory requirements, pharmacopeial standards, and the specific
characteristics of the drug product.

Types of dosage forms and considerations to take into account whilst developing a robust dissolution method:
There are two main types of solid dosage forms in terms of mode Immediate Release Dosage Form: Extended-Release Dosage Form: Delayed-Release Dosage Form:
of release of API from the formulation.
Immediate release dosage forms are intended to release the active Extended-release dosage forms are designed to release the active Delayed release dosage forms are designed to release the
1. Immediate/Conventional release dosage forms pharmaceutical ingredient (API) immediately upon administration to pharmaceutical ingredient (API) over an extended period of time, active pharmaceutical ingredient (API) after a certain amount
2. Modified release dosage form achieve a rapid onset of action. To allow immediate release of API, typically over several hours or even days. The extended-release of time or after passing through a specific region of the
Further, Modified release dosage form can be extended release disintegrant like sodium starch glycolate Polyvinylpyrrolidone (PVP) mechanism is achieved through the use of the hydrophobic gastrointestinal tract. The subsequent release is similar to that
or delayed release, with each having further subclasses. Some etc. are widely used in these type of dosage forms which provides polymer matrix, which acts as a diffusion barrier to control the of an immediate release dosage form or extended release.
examples of these are site specific release, timed release, pulsatile in instantaneous disintegration of tablet after administration. release of the drug over time. As water enters the matrix, it slowly The delayed release mechanism can be achieved through the
release (release of drug in sudden bursts at specific time intervals), penetrates and dissolves the drug, which then diffuses out of the use of enteric coatings which is designed to remain intact in
and biphasic release (first phase being sudden release then 2nd matrix and is released into the surrounding medium. the acidic environment of the stomach, but to dissolve rapidly
phase with slow extended release to maintain therapeutic effect) The specific shape of the dissolution profile can vary depending in the more alkaline environment of the small intestine. This
etc. on the specific formulation and release mechanism, but generally delayed release allows for targeted drug delivery to specific
an extended-release dissolution profile should show a controlled regions of the gastrointestinal tract and can improve drug
release of the drug over an extended period of time, with minimal efficacy and reduce side effects.
Immediate fluctuations in drug release rate. This ensures consistent and Examples of delayed-release systems include repeat action
Release effective drug delivery over the intended dosing interval. tablets and capsules, and enteric-coated tablets where timed
Solid Dosage
Extended-
release is achieved by a barrier coating.
Form
Release

Modified
Release

Delayed-
Release

Figure 4: Types of Solid Dosage Forms.

Figure 5: Immediate release dissolution profile showing Figure 6: Extended-release dissolution profile of a drug product Figure 7: Delayed-release dissolution profile of a delayed
instantaneous release of acetaminophen within 15 minutes showing slow and steady release of API for 24 hours using release capsule containing enteric-coated beads. At the
using 0.1M HCl as a dissolution medium and USP 2. phosphate buffer as a dissolution medium and USP 2. beginning, there is a lag time during which no drug is
released, followed by a gradual increase in drug release
over time.

Key requirements for above mentioned dosage forms:

• Dissolution rate – Immediate release formulations should have a rapid dissolution rate to ensure that the API is released quickly upon to ensure the controlled and sustained release of the API. For example, hydrophilic polymers, such as hydroxypropyl methylcellulose,
administration. The dissolution rate should be determined using appropriate methods, such as USP apparatus 1 or 2. Extended-release can be used to form a matrix that controls the release of the API over time. Excipients used in delayed release formulations should
formulations should have a controlled and predictable release profile to ensure that the API is released at a constant rate over the desired be carefully chosen to ensure the delayed release of the API. For example, enteric coatings made of polymers like methacrylic acid
time period. The delayed release formulation should have a mechanism to delay the release of the API until the desired time or location. This copolymers can be used to delay the release of the API until it reaches the desired location in the gastrointestinal tract.
can be achieved through the use of enteric coatings or pH-sensitive polymers.
• Appropriate choice of manufacturing process – The manufacturing process used to produce the formulation should be appropriate for
• Consistent and reproducible release profile – The release profile of the API from the formulation should be consistent and reproducible to the specific drug product and should ensure consistent and reproducible quality.
ensure the efficacy and safety of the drug product. Variations in the release profile could result in inconsistent therapeutic effects or adverse
• Stability – The formulations should be stable under appropriate storage conditions to ensure that the API remains active and effective
events.
throughout the shelf life of the drug product.
• Uniformity of dosage units – The dosage units, such as tablets or capsules, should be uniform in weight, size, and composition to ensure
• Quality control – Quality control procedures should be established to ensure that the formulation meets the required quality standards.
consistent dosing and release of the API.
These procedures should include testing for purity, potency, and stability.
• Compatibility with excipients – The excipients used in the formulation should be compatible with the API and each other to ensure the
• In vitro-in vivo correlation – In vitro-in vivo correlation (IVIVC) studies may be required to establish the relationship between the in vitro
stability and efficacy of the drug product. Any incompatibilities could lead to degradation of the API or reduced efficacy.
release profile and the in vivo performance of the drug product. This can help ensure that the formulation is effective and safe for its
• Appropriate choice of excipients – Excipients used in immediate release formulations should be carefully chosen to ensure the rapid intended use.
dissolution and release of the API. For example, disintegrants, such as croscarmellose sodium or sodium starch glycolate, can be added to the
formulation to aid in rapid disintegration and release of the API. Excipients used in extended-release formulations should be carefully chosen

Conclusion:
Dissolution is a critical test required to demonstrate the in-vitro release of drug from the drug product and as mentioned above there At RSSL, we can support you with all the analytical needs required for your product. RSSL expertise is not limited to only this, we
are several critical parameters to watch when developing a dissolution method. have an expert team to support you with product development from start to end of the drug product life cycle.

References: Internet based contents and various research papers

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