Low-dose drug content uniformity prediction and process selection

In recent years, scientists in the field of drug discovery have studied many very effective small molecule drug candidates, but the pharmacological effects of such drugs can be very low
effective doses.
This low-dose drug presents significant challenges
in product design and optimization.
In the new regulatory environment, how to increase production while ensuring product quality and safety is another great challenge
for these drugs.

In the development of new drug preparations, when the drug development dose is low, it may lead to a very low
drug load in the preparation.
According to MCS, when the drug load in the preparation is extremely low, the relevant physical properties of the intermediate and the final product, such as the compressibility and fluidity of the intermediate particles, are affected
by the poor physical and chemical properties of the API.
However, when the dosage of the preparation is low to a certain extent, it will bring new problems and challenges
.

The active ingredient in low-dose pharmaceutical formulations is usually highly active, with high bioavailability and narrow therapeutic windows
.
Low-dose pharmaceutical formulations are formulations
with a drug load of less than 1% (USP), 2 mg, or 2% (British Pharmacopoeia).

Low-dose pharmaceutical preparations generally have the following characteristics:

Very low unit drug content;

Large excipient/drug ratio (can be as high as 500 to 50,000);

The production process is very vulnerable to loss and pollution;

Extremely sensitive analytical methods and extremely fine pretreatment methods are required, and good recovery rates are obtained;

It is likely to be a BCSI or class III drug;

The content uniformity of the final product and the stability of the product in production and storage are high
.

The characteristics of low-dose drugs also determine the problems that may be encountered in the development of formulation processes:

       understanding patients’ needs;

       selecting manufacturing platform technology;

       achieving blend uniformity;

       achieving dosage unit uniformity;

       understanding critical product quality attributes;

       controlling critical process parameters;

       understanding process analytical technology (PAT);

       controlling excipients for manufacturability and product stability;

       optimizing container/closure system for product stability;

       achieving quality by design (QbD) and risk assessment

In the face of the regulation of low-dose drugs, for slightly larger preparations, such as 5mg specifications, does not have the above risks or problems?

From the perspective of process, low-dose drugs are very easy to cause the content uniformity of
the final product.
Figure 1 establishes the correspondence between API specifications and API particle size to meet the requirements
of final product content uniformity.
Based on the specifications determined by the formulation and the geometric standard deviation sg if the measured API particle size distribution conforms to the lognormal distribution, the appropriate API particle size distribution
can be inferred from the model.
For example, for the granulation of 1mg specification, the geometric standard deviation sg=4, it can be deduced that the API particle size is about 8μm
.
For the above prediction model, the definition of API granularity and the selection of processing methods can be given as a basis
.

Of course, as can be seen from Figure 1, the smaller the specification and the larger the geometric standard deviation of the particle size, the smaller the particle size of the API that may be required to meet the requirements for content uniformity of
the final product.
From the perspective of risk assessment, it is not that the development specification is above the definition of low dose, which is far away from the challenges of low-dose drugs, but the difficulty of possible development is reduced and the risk is reduced
.

For low-dose varieties, the ability to micronize APIs is critical to the possibility of obtaining a homogeneous solid pharmaceutical product, as low doses require as much micronization as possible to produce more servings of API well mixed
with excipients.
If the compound cannot be micronized or polymorphomorph changes occur during grinding, then this API treatment may not be feasible
.

Figure 2 details the process options
for low-dose drug development.

The first thing to determine is whether the API can be micronized, and if the compound cannot be micronized, a strategy
involving drug dissolution must be considered.
For example, dissolve prescription amounts of API in molten polyethylene glycol (PEG) or Gelucire lipid matrix
.
The molten mixture is then filled into capsules, or excipients are fused with dissolved drugs, or used as binders to obtain granules
.
They can then be packed into capsules or pressed into tablets
.
The drug dissolved in the capsule filling matrix needs to be compatible
with the housing material.
Lipid-based systems
of different polarities are commonly used here.
When the capsules are filled with liquid, excellent content uniformity can
be achieved.

For APIs that can be micronized, developing doses greater than 0.
5mg may lead to the development of DC (direct pressing) or RC (rolling) processes, which are commonly used technology platforms
by most pharmaceutical companies.
In both processes, mixing uniformity before tablet pressing or rolling is key
.
A homogeneous mixture
with a limited tendency to separation must be obtained through careful selection of excipients and mixing processes.
Granulation techniques often reduce the likelihood of separation of the mixture and improve overall flowability
.

For drugs that are not suitable for DC/RC or are developed at doses between 50 and 00 μg, wet granulation or fluidized bed granulation
can be selected if they are wet stable.
If the drug is sensitive to moisture, organic solvent granulation or fluidized bed granulation
can be used.
Compared to wet granulation, fluidized bed granulation has a shorter contact time with humidity, and fluidized bed granulation
can be preferred when choosing between the two.

From an industrial and regulatory point of view, the main disadvantage of organic solvent granulation is that all compounds first dissolve and then precipitate
when the solvent evaporates.
The evolving solid form becomes critical to the quality properties of the final drug product, as the method can lead to the formation of another polymorphic or even amorphous material
.
API crystal form stability is risky
.

For pharmaceutical products with very low API content (Figure 2 defines it as less than 50 μg), all of the above formulation strategies can be used in principle, even if it is difficult to obtain suitable content uniformity at very low doses
.
One way to avoid this is by producing a granule with a relatively high API content, mixing it with placebo granules and pressing it into tablets or filling into
capsules.
For very low doses, the possibility of dissolving the drug into solvents or polymers should be evaluated, which can also be used for liquid filling
of capsules.

In addition to the above introduction to select the particle size of the API to meet the content uniformity of low-dose drugs through the prediction method, the appropriate development process can also be selected through the physical and chemical properties of the API; For low-dose drugs, it is also important
to choose the appropriate excipient.

Olanzapine is an atypical antispermia drug developed by Eli Lilly and belongs to the Biopharmaceutical Classification System (BCS) class II drugs
.
Because of its small solubility and low proportion in the preparation, the original tablet adopts a wet granulation process
.
The article "Using lactose carrier adsorption to improve the mixing uniformity of powder direct pressure olanzapine tablets" made such a design, prepared a prescription with an API load of 2.
5%, and the drug load is low with the risk of mixing uniformity and content uniformity, and if the powder direct pressing process is used, the risk value is directly full
.
Through different models of lactose sieves mixed with API, it was found that spray-dried lactose with a rough circular surface attracted API particles to fill into the pores and grooves on the surface, and multiple coverage, reducing the risk of
agglomeration of free API particles.

The article also introduces the preparation of different particle sizes of API and lactose mixing, and the study found that as the particle size of the API decreases, the better the mixing uniformity of the premix, which is actually consistent with the above prediction, the results are shown in Figure 4
.

For low-dose drugs, in order to meet their mixing uniformity and content uniformity, micronized powder or other particle size reduction methods
are often used.
However, micronized APIs are also an energy-intensive process, and they also pose a risk of physicochemical stability under the premise of
causing losses to APIs.
The development of preparations always encounters dilemmas, and always pushes the project forward in the decision.
.
.

References

       1.
Methodology of oral formulation selection in the pharmaceutical industry

2.
Using lactose carrier adsorption to improve the mixing uniformity of powder direct pressure olanzapine tablets_Li Xuanzhe

       3.
A Quality By Design Approach to Scale-Up of High Shear Wet Granulation Process

4.
Formulation and Analytical Development for Low-Dose Oral Drug Products

5.
Martin Physical Pharmacy and Pharmacy (book)

6.
Key points of quality control of low-dose solid pharmaceutical preparations