Discussion: Development of dissolution methods for oral solid preparations

PART.
01 Background Oral solid preparations can generally be divided into regular release preparations (Immediate Release, IR) and Modified Release preparations (Modified Release, MR)
.
The design goal of IR formulations is to allow the drug to dissolve freely in the gastrointestinal tract, rather than to delay or prolong the dissolution and absorption of the drug after administration
.
Normal-release preparations may be rapid dissolution (rapid dissolution) and very rapid dissolution (very rapid dissolution), or slow dissolution
.
For fast-dissolving IR preparations, ICHQ6A is defined as the dissolution volume within 15 minutes of no less than 80% of the labeled volume in the medium of pH 1.
2, 4.
8, 6.
8 (the definition in FDA GUIDANCE is slightly deviated, see appendix)
.
Modified-release preparations include a wider range of oral pharmaceutical preparations, such as enteric-coated tablets, sustained-release preparations, and controlled-release preparations
.
The solid preparation must first dissolve in the gastrointestinal tract in order to exert its efficacy, and then the drug molecules are absorbed into the blood through the gastrointestinal mucosa, and then reach the target position through the circulatory system to play a role, as shown in Figure 1
.
The dissolution rate of the drug may affect the bioavailability, which in turn affects the efficacy of the drug
.
Therefore, the dissolution test is very important for the development of oral solid preparations, which runs through the entire process of drug development
.
At present, there are only a few oral solid preparations that may be more appropriate to test the in vitro performance of the product by the disintegration time limit, and the rest of the products require dissolution testing
.
Figure 1: Schematic diagram of the absorption steps of solid oral dosage forms PART.
02 Purpose of dissolution test Dissolution test is a tool used to compare the in vitro performance of oral solid dosage forms
.
One of the purposes of dissolution testing is to assist in the design and screening of prescriptions
.
In the early stage of formulation development, when the dissolution test of tablets or capsules has not reached the standard, it may indicate the need to adjust the prescription and process, or the dissolution method
.
There are many factors that affect the dissolution, such as the composition of the powder, the physical properties of the raw and auxiliary materials (the particle size distribution of the raw and auxiliary materials, the density of the particles, the viscosity grade of the polymer, the source of the auxiliary materials, etc.
), the manufacturing process (wet granulation/dry preparation) granulation / direct compression, selected), dissolution method granulation parameters, the lubrication time, tableting pressure, coating parameters, and other external environment during the dissolution test
.
We should understand the drug release mechanism and identify the behavior of the formulation through the dissolution experiment.
In addition to the content analysis of the dissolution results, we must pay attention to the observation of experimental phenomena, such as the floating of the formulation or powder, the change of disintegration, and the accumulation of cones
.
These simple phenomena may have far-reaching implications
.
Another purpose of dissolution test is to carry out quality control (Quality Control) between different batches of products
.
When sufficient pharmacokinetic (PK) data of different batches of products with different dissolution profiles are obtained, it is possible to establish in vivo and in vitro correlations (IVIVC) through reasonable dissolution tests
.
After IVIVC is established, the results of in vitro dissolution can be used as a surrogate for the product's in vivo performance
.
On the basis of a clear IVIVC, the dissolution results can provide the basis for the bioequivalence (BE) test exemption for the registration and application of certain BCS class I and class III rapid dissolution products, as well as the scale-up production and major changes after approval
.
Such a dissolution test can not only reduce the review time of the regulatory authorities, but also reduce the time and money that manufacturers consume in the BE test
.
However, it should be noted that the establishment of IVIVC is very difficult.
The establishment of IVIVC requires a systematic understanding of the physical and chemical properties of drug molecules, biopharmaceutical properties and formulation design and its interaction with the gastrointestinal tract, although there are some successful cases , But due to the complexity of dissolution and absorption in the body, there are still many products that cannot establish in vivo and in vitro correlation
.
In the absence of an accurate IVIVC, the following points should be considered when using dissolution testing as a quality control method: 1.
The dissolution data is method-dependent.
For the same product, different dissolution methods may result in significantly different dissolutions.
Data
.
Therefore, the development of dissolution methods is very important
.
2.
Generally speaking, dissolution standards are usually set based on BE/BA batches
.
It is meaningful to compare the dissolution data of different batches of the same product and the dissolution standards previously set for quality control
.
Generally, it is not necessary to compare the dissolution of different products horizontally (except for the biowaiver for bioequivalence exemption for generic drugs)
.
3.
The dissolution method should have appropriate discrimination, should be able to detect major changes that may cause bioinequivalence, and should tolerate normal changes in routine production to prevent unnecessary product scrapping
.
PART.
03 Development of dissolution methods The most commonly used methods for solid oral preparations are the basket method (Apparatus Ⅰ) and the paddle method (Apparatus Ⅱ), as shown in Figure 2
.
The commonly used speed of the basket method is 100 rpm, and the commonly used speed of the paddle method is 50-75 rpm
.
For solid preparations that float, such as capsules, the basket method may be more appropriate.
If the paddle method is to be used, a settling device should be used to prevent floating
.
For tablets, the paddle method (Apparatus Ⅱ) may be used more
.
It should be noted that for the paddle method, the hydrodynamic properties in the dissolution cup are highly heterogeneous, and the position of the drug at the bottom of the cup may change the dissolution rate
.
If the tablet deviates from the center of the dissolution cup, the hydrodynamic properties may change, which mainly affects the release of the drug in the disintegration process
.
Figure 2: Schematic diagram of the basket method and paddle method device.
Before selecting the appropriate dissolution medium, the physical and chemical stability of the active ingredient of the drug needs to be determined
.
Before deciding on the composition of the dissolution medium, it is necessary to fully evaluate the impact of buffer and pH
.
If it is necessary to add surfactants, it is also necessary to study the influence of different surfactants on the solubility and stability of the drug
.
The selection of dissolution medium must meet the sink conditions to ensure a sufficiently large concentration gradient during dissolution and more accurately reflect the nature of the formulation itself
.
Prior to this, it is necessary to determine the saturated solubility of the drug in different pH media.
Solubility is one of the most important physical and chemical properties of the drug.
The determination and improvement of drug solubility is a work that must be done in the process of formulation development
.
People usually think that the solubility determination is a trivial task, but it is very challenging to accurately determine the solubility.
Many factors will affect the solubility determination, leading to deviations in the results
.
The medium for measuring equilibrium solubility includes buffers with a pH range of 1.
2-7.
4, simulated gastric juice and intestinal juice, and purified water
.
In the process of determining the saturation solubility, the pH change of the supernatant should be monitored during the test, and the pH needs to be adjusted if necessary
.
If necessary, it is necessary to study the influence of different surfactants (type and concentration) on the solubility of the drug, evaluate the influence of ionic effects on the solubility, and study the solubility of the drug at other temperatures, such as 25°C
.
Precautions for solubility determination: ●Whether the solute is degraded; ●Solid state (crystal form) of the solute; ●Detect and correct the pH (pH-solubility) of the solution; ●The electrolyte should preferably not contain ions in the solute to avoid Common ion effect; ●The buffer and electrolyte themselves may form salts with lower solubility with the ionized drug.
After the test, determine whether the remaining solid contains the components of the buffer and electrolyte, and evaluate whether the salt type has changed
.
When conducting solubility experiments, pay attention to the observation of experimental phenomena, especially when there is dissolution and precipitation, the risk of crystal or salt conversion is greater, and special attention should be paid
.
PART.
04 Dissolution method development report In order to support the selected dissolution method, it is necessary to provide a dissolution method development report in the registration application materials.
The development report should provide the following content: 1.
The solubility data of the API within the physiological pH range
.
Because the solubility data is the basis for choosing a suitable dissolution medium and deciding whether or not a surfactant is needed
.
2, the selection device and method, the dissolution medium, the pH medium, medium volume, stirring speed, determination, sink conditions, selecting the settling device (if necessary), the choice of enzyme (if necessary), and the like
.
If a surfactant is added, data support for the selected type and amount of surface activity needs to be provided
.
3.
Sampling time point: Generally speaking, for immediate-release preparations, choose 10, 15, 20, 30, 45, 60, 90 minutes; for sustained-release preparations, choose 1, 2, 4, 8, 12, 24h
.
4.
Prove the distinguishing ability of the selected dissolution method: You can produce products of different quality by deliberately adjusting production variables (such as adjusting key material attributes (CMAs) and key process parameters (CPPs) by 10-20%), and then go Comparison of its dissolution proves the distinguishing power of the dissolution method
.
The figure below shows the effect of adjusting tablet hardness and binder viscosity on dissolution
.
Figure 3: The influence of tablet hardness and adhesive viscosity on dissolution sometimes can be over-differentiated dissolution methods, as shown in Figure 4, although the in vitro dissolution of the produced sample and the reference sample after the process change is significant Difference, but its in vivo bioavailability is basically the same
.
Figure 4: Excessively differentiated dissolution method Of course, in the actual product development process, the immediate release formulation may dissolve too quickly, and it is impossible to find a distinguished dissolution method
.
At this time, it can be implemented according to ICH Q6A Decision Tree #7.
As long as the dissolution rate does not significantly affect the bioavailability, and the changes in the formulation and process do not affect the dissolution rate, there is no need to consider the discrimination power of the dissolution method too much
.
However, at this time, it is necessary to collect the dissolution data of the product in multiple dissolution media (such as pH 1.
2, pH 4.
5, pH 6.
8) to prevent problems in the application process
.
5.
Provide other verification data of the dissolution method, such as system applicability, method durability, whether the medium needs to be degassed, medium pH durability, instrument temperature durability, filter membrane adsorption test, solution stability study, repeatability test, intermediate Precision research, automatic and manual sampling verification, and content analysis method verification (specificity, linearity and range, recovery rate, etc.
)
.
PART.
05 Dissolution method quality control time point and selection of acceptance criteria When setting dissolution quality control standards, the clinical performance of the product is the first and most important consideration
.
Therefore, the in vivo data and in vitro dissolution data of key clinical batches should be combined to formulate dissolution standards (time points and dissolution limits)
.
Two examples of IR preparations: Case 1: As shown in Figure 5, compared with the other two batches, the clinical batch has the highest dissolution rate, and the dissolution profile of the clinical batch is similar to that of the test batch 2 (f2 factor = 56.
3 ), the dissolution profiles of clinical batch and test batch 1 are not similar (f2 factor = 44.
7)
.
The clinical BE test showed that, compared with the clinical batch, the BE of test batch 1 just met the BE acceptance criteria
.
Therefore, when formulating the dissolution standard, the dissolution of batch 1 can be considered as the lower limit
.
It should be noted that the reference of factor f2 is best based on in vivo data, because how similar the in vitro data of two batches of bioequivalent products will be, and how much in vitro data will there be for two batches of bioequivalent products We don’t know if they are not similar
.
Figure 5: Dissolution curves of three batches of products with the same bioavailability.
Case 2: As shown in Figure 6, batch A is known to be a key clinical batch and has been proven to be safe and effective.
Batch B and batch A are biologically different Effective
.
So when formulating the dissolution standard, if 80% is the dissolution limit, 30min cannot be selected as the quality control point.
This will cause two batches of products to be accepted at the same time, and batch B can be rejected by selecting 15min as the quality control point
.
Figure 6: Dissolution of two batches of products that are not bioequivalent.
At the same time, ICH Q6A pointed out that if the dissolution cannot be used as a sensitive indicator of product quality control compared with the disintegration test, it may be necessary to use disintegration as a quality control standard
.
In summary, the solubility measurement and the development of dissolution methods are very meticulous work.
The solubility measurement lays the foundation for the selection of the dissolution method.
The dissolution experiment runs through the product development process.
The experiment must be carried out under the guidance of laws and regulations to get accurate Experimental data
.
Appendix: Rapidly dissolving: Using the method of USP device I or II, in an aqueous medium of <900ml, more than 85% of the drug should be dissolved within 30 minutes; and for very rapid dissolving, there should be within 15 minutes More than 85% of the drug dissolves
.
References: 1.
"Guiding Principles of Dissolution Test for Oral Solid Oral Dosage Forms" 2.
Yihong Qiu et al.
Developing Solid Oral Dosage Forms_ Pharmaceutical Theory and Practice 3.
Pharmaceutical Research, Vol.
19, No.
7, July 2002 4.
Waiver- of-In-Vivo-Bioavailability-and-Bioequivalence-Studies-for-Immediate-Release-Solid-Oral-Dosage-Forms-based-on-a-Biopharmaceutics-Classification-System.
-Guidance-for-Industry 5.
Q6A: Quality Standards: Testing methods and acceptance standards for new raw materials and new drug preparations: chemical drugs