Over the last 15 years, the pharmaceutical industry has discovered and developed increasingly more low-dose drug products. From a formulation perspective, a low-dose drug product means low drug concentration, or low drug load, which can be less than 0.01% (w/w). The dose strength of a low-dose product can be as low as 0.25 mg. In other words, the low-dose formulation likely has a very high ratio of excipients to drug substance. The ratio of inactive ingredients (excipients) to drug can be between 1000 and 10,000, which is significantly different from a common drug product.
Although development of new normal-dose and low-dose drug products follows a similar path), the increase in potency and decrease in dose with low-dose drug products creates increasing challenges. The following characteristics are some of the hurdles which pharmaceutical scientists and production operators must meet (during the formulation and process development of a low dose formulation) to fulfill , the stringent regulatory standards.
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Low potency due to manufacturing loss
Difficulty achieving content uniformity due to low drug concentration
Instability due to the huge ratio of excipients to drug substance (which increases
the likelihood of incompatibility)
Chemical instability due to a micronized drug having greater surface exposure to
excipients, moisture, and manufacturing equipment
Instability due to physical transformation to a less stable solid form during
manufacture or long-term storage.
The nature and properties of a drug substance dictate the design of formulation composition and the choice of manufacturing platform technology. The most commonly used manufacturing platforms for solid oral dosage form include:
high-shear wet granulation;
fluid bed granulation;
One of the most important quality attributes for low-dose drugproducts is uniformity of dose unit. Usually, dose strength of a drug product is important in selecting a manufacturing platform technology. A simple decision tree on platform selection according to dose strength is described in Fig. 2.3 and is discussed below.
Direct compression is an attractive platform for manufacturing tablet drug products. However, developing a low-dose drug product using direct compression poses great challenges to consistently producing high product quality. These challenges may range from control of raw materials (e.g., drug substance, excipients, and packaging components) to design of formulation and manufacturing process. Major challenges discussed in the following sections include control of the physical properties of drug substance, mixing homogeneity, segregation, and lubricity. Successful development of low-dose tablet formulations using direct compression platform technology depends on careful consideration of several factors:
† drug substance properties;
† excipient properties;
† optimization of the compressibility of the powder blend;
† optimization of the flowability of the powder blend;
† optimization of the lubricity of the powder blend.
Formulation design is based on the physical, chemical, and biopharmaceutical properties of a drug substance. A formulation for direct compression is composed of active pharmaceutical ingredients and other inactive ingredients such as fillers, binders, disintegrants, flow aids, and lubricants. Simplicity is the basis of good formulation design. Minimally, a direct compression tablet formulation must meet requirements for manufacturability, uniformity of dose, physical and chemical stability, appropriate drug release profiles, and bioavailability. In addition, the formulation must meet many quality standards and special requirements to ensure the efficacy and safety of the product
for a low-dose formulation, the particle size of a drug substance is the first attribute to evaluate for impact on blending and content uniformity. It can be necessary to mill or micronize the drug substance to reduce its particle size. As part of the selection of the milling operation, examine the physical and chemical stability during and after milling. Since aggregation is a common issue for micronized powders, make efforts to control the aggregates of a fine drug substance. This can reduce difficulties during material handling and product manufacture. In some cases, it may be important to assess the surface area of the drug substance in addition to particle size. The combination of particle size and surface area of the drug substance may provide better control for final uniformity of the dose unit and long-term product stability. To assess the impact of drug substance particle size and size distribution on a formulation, prepare two to three batches of drug substance with different mean particle sizes for formulation and process evaluation. This helps establish a specification to control particle size and size distribution of the drug substance. Chemical properties are important when designing a formulation for direct compression. If a drug has tendency to oxidize, mixing an antioxidant with the drug substance may not be an effective way to place the antioxidant in close proximity to the drug substance to prevent the oxidation reaction. Similarly, direct compression
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cannot offer an optimum way to incorporate a wetting agent into a formulation. Thus, it may be necessary to revisit the formulation strategy for such a compound
Generally, when developing a direct compression formulation, efforts to match particle size distribution and density of drug substance to the major excipients help minimize segregation. Meanwhile, the particle size distribution should be relatively narrow (100 mm range) to ensure a satisfactory flow for the blend. The commonly used excipients for preparing direct compression blends can be categorized by the function performed in a formulation. Excipients are grouped into six functionalities in direct compression blends:
† fillers-binders (so-called carriers, diluent, and bulking agent);
† flow aids or glidants;
† stabilizers (pH modifiers and antioxidants);
However, some excipients have multiple functions. For example, microcrystalline cellulose can function as a filler, a binder, and a disintegrant. As seen in Table 7.3, a typical low-dose formulation could include more than 85% filler-binders. Thus, physical and chemical properties for these specialty excipients are extremely important in a low-dose formulation for manufacturability, product performance, and longterm stability. Because the poor physicomechanical properties of components are not altered during manufacture as they are in the wet or dry granulation process, critical material properties and their impact on product quality attributes should be well characterized and understood.23 Discussion in this section will focus on fillers- binders. For those requiring more information on excipients, several excellent books and review articles are available in the literature.24-27 There are many commercially available direct compression filler-binders. The most commonly used filler-binders include spray-dried lactose, mannitol, microcrystalline cellulose, pregelatinized starch, and dibasic calcium phosphate. Many factors affect the selection of a filler-binder for a direct compression tablet formulation. The
most important requirements for a directly compressible filler-binder used in a lowdose
formulation are listed below:
† high compactibility and compressibility to ensure that the powder mixture can
be compressed efficiently and the compacted tablet will remain bonded after the
release of the compaction pressure;
† good flowability as a result of appropriate particle density, size, and size distribution
to ensure that the powder blend flows homogenously and rapidly during
low lubrication sensitivity to reduce potential over-lubrication;
† good compatibility with drug substance to ensure long-term product stability;
† good physical and chemical stability to ensure product quality attributes are
unchanged during storage;
† good batch-to-batch reproducibility of physical and mechanical properties to
ensure constant quality materials;
† good commercial availability and regulatory acceptability throughout the world.
Certainly, not a single excipient meets all the optimum requirements. Therefore, it is
common to use a combination of two filler-binders in order to obtain a formulation
with excellent tableting properties.
The goal of this study is to determine the optimal choice in each excipient
category. The common formulation factors may include:
† filler-binder-lactose, mannitol, microcrystalline cellulose (MCC), or starch;
† disintegrant-crospovidone, sodium starch glycolate, or sodium croscarmellose;
† flow aid-talc or colloidal silicon dioxide;
† lubricant-magnesium stearate, stearic acid, or sodium stearyl fumarate