Andriy Kuzmov Scientist, Scientific Affairs Catalent
Julie Doboszczak Product Marketing Manager, Rx Oral Dose Catalent
William Wei Lim Chin Manager, Global Scientific Affairs Catalent
Call it the “oral paradox”: oral drug delivery dominates medicine administration because it is convenient and non-invasive. But that delivery often offers poor oral bioavailability. Developing more bioavailable formulations remains a challenge to scientists creating new oral dosage forms. As poorly soluble drug molecules are increasingly prevalent in the development pipeline, innovators are turning to technologies, such as micronization, to improve the bioavailability and solubility of these challenging compounds.
With 34 new small molecule drugs approved in 2021 (68% of all U.S. FDA approvals), they continue to account for the majority of newly approved treatments.1 The use of high throughput screening, a focus on potency, and targeting of complex binding pockets has resulted in the increased number of lipophilic high molecular weight compounds with poor solubility in development pipelines.2,3 While estimates vary, a review by GSK, for instance, showed that nearly 70% of its pipeline candidates were poorly soluble.4 Solubility is one of the determinants of oral bioavailability and needs to be addressed during development. Several enabling technologies could improve both solubility and bioavailability. Particle size reduction through micronization is one such technology. It is convenient and cost-effective, with several advantages summarized in Table 1:
Micronization of DCS class II drugs
The developability classification system (DCS) helps to quickly assess the bioavailability challenges that a compound might face after oral administration and expands upon the ideas introduced by the biopharmaceutics classification system (BCS). While the BCS was proposed as a regulatory tool to support the use of biowaivers, the DCS was created as a tool to facilitate the development of orally administered drug products. Using information such as the expected dose, solubility, and permeability, the DCS categorizes compounds into one of five classes, shown in Figure 1. When complemented with physiologically based pharmacokinetic (PBPK) modeling, the input of gastrointestinal hydrodynamics, dissolution and postabsorptive disposition parameters can predict the impact of diff erent particle sizes on the rate and extent of oral absorption.5
Compounds that fall into DCS class I have good solubility and permeability and can be successfully developed using traditional immediate-release formulations. However, compounds that fall into DCS class II are considered poorly soluble, but have good permeability and are most likely to benefit from solubility-enhancing formulation approaches. Class II is split into two subcategories: class IIa compounds benefit from techniques such as micronization that improve the dissolution rate of the API; whereas class IIb compounds will require formulations such as amorphous solid dispersions (ASDs) or lipid-based formulations that deliver the API to the gastrointestinal (GI) tract in a solubilized state.
Class IIa compounds have good permeability, so the administered dose can be fully absorbed given a high dissolution rate. The DCS provides an equation to calculate a theoretical target particle size for a compound below which the dissolution rate will not limit drug absorption.6 Compounds that fall into DCS IIb, but are near the border of the solubility-limited absorbable dose (SLAD) line may benefit from co-micronization, where a small percentage of surfactant is mixed with the API before the micronization process begins.
Applications beyond solubility enhancement
Beyond enhancing bioavailability by improving the dissolution rate of APIs, micronization can help develop products where particle size control is essential for performance. For example, dry powders for oral inhalation, oral suspensions, and ocular suspensions require precise control of particle size to ensure consistent performance of the finished dosage form. Micronization is an ideal methodology to achieve this.
Particle engineering for inhalation
Historically, low dose oral inhalation using pressurized metered dose inhalers has been used for the treatment of pulmonary conditions such as asthma and chronic obstructive pulmonary disease. However, there has been growing interest in delivering higher doses to the lungs for both local and systemic treatments. Micronization techniques can enable development of dry powders for oral inhalation. The particle size of the dispersed powder is critical and can impact the deposition profile of the powder within the lungs. Larger particles tend to get trapped in the throat and upper airways and not reach deep lung targets.
Oral and ocular suspensions
When developing oral and ocular suspensions, the particle size of the suspended phase is one factor determining the suspension’s performance, particularly for low-solubility compounds. In addition, the dispersion of these API particles in the suspending medium should be uniformly distributed without any signs of sedimentation. Particle size has a direct effect on maintaining a uniform suspended phase.7
High potency APIs
Micronization is ideal to aid development of highly potent APIs (HPAPIs) that require low dosage, although assuring consistent content uniformity can be challenging for a drug load of less than 1% API in a dry pharmaceutical preparation. Optimized blending/mixing techniques and proper selection of inert excipients or fillers, such as calcium phosphate or mannitol, can help ensure the content uniformity of the blend.
Up to 25% of all drugs are classified as highly potent. This number will continue to rise as HPAPIs are increasingly developed as targeted treatments in oncology, metabolic disorders, and autoimmune diseases.8 The need for robust manufacturing operations to contain and handle highly potent compounds safely will also need to increase to match demand. While several isolator systems exist, the use of hard wall isolators is known to provide maximum containment for the manufacture of HPAPIs, and allow flexible clinical- to commercial-scale jet milling operations at occupational exposure limit (OEL) values as low as 0.05 μg/m3.
Overview of milling techniques
The pharmaceutical industry routinely uses several types of milling techniques. The specific milling method depends on the target particle size of the micronized powder. Smaller particle size specifications (<10 μm) will require the use of a jet mill, and in comparison, larger particle size specifications (>30 μm) can be achieved using mechanical techniques such as hammer, pin, or conical mills. While a smaller particle size leads to an improved dissolution rate, smaller particles have higher surface energy, leading to poor flow and agglomeration concerns. It is therefore crucial to understand the bulk powder behavior of a given API at varying sizes, to determine how a smaller target particle size can impact downstream processing and manufacturability of the micronized API. Co-micronization of the API with a surfactant can help improve powder flow properties, wettability, and solubilization of the API.
Mechanical milling
Traditional mechanical techniques such as hammer, pin and conical milling utilize moving parts to break the material into smaller particles. Hammer mills use a spinning rotor inside a drum with free-swinging hammers that pulverize the API as it is fed into the drum. Pin mills have a grinding chamber with two plates, one moving and one stationary, fitted with pins on their faces. The API is fed into the chamber and broken up by striking the moving plate and being ground between the pins. Conical mills utilize impellers to force the powder through a conical screen with a predetermined mesh size. These methods are beneficial for breaking up large particles into 50 to 500 μm particles. However, since they utilize moving parts, wear and tear on the equipment is inevitable with repeated use.
Jet milling
In jet milling, the material is manually loaded into the feed funnel, and compressed nitrogen or air is used to suspend the powder in a high-velocity gas stream within the grinding chamber. Jet mills rely on the impact and attrition of the API brought on by high-velocity collisions between particles within the grinding chamber. Centripetal forces separate the larger particles from the smaller particles, where smaller particles move with the escaping gas towards the center of the mill and the larger particles recirculate on the periphery of the milling chamber. Jet milling is the preferred method for micronization when the target particle size specification is less than 10 μm. For jet milling, critical process parameters include the feed rate, milling pressure, venturi pressure, and API characteristics such as starting particle size and morphology. Understanding the interplay between these factors and their effects on the final particle size distribution will ensure development of a robust process.
Cryogenic milling
Brittleness is one of the few factors that determine the effectiveness of micronization on a material. While hard materials require high energy input levels to break the particles, any newly created fractures can propagate through the material’s weak points, leading to breaks. If the material is soft or elastic, micronization is challenging at ambient temperatures. Cryogenic milling takes place at temperatures as low as -50°C, which increases the material’s brittleness, allowing the micronization of low melting point APIs, heat-sensitive APIs, or excipients that are too soft to process at room temperature.
Impact of co-micronization on powder properties
Besides the shape and size of the particle, the milling process can affect the surface properties of both APIs and excipients, which influence the drug’s performance.9 The increase or decrease of the powders’ surface energy depends on the equipment, processing methods and conditions.10-12 These changes can affect the tendency to agglomerate, where particles stick either to each other or to a surface, which in turn affects the bulk handling and downstream processability during manufacturing. Co-micronization of an API with a lubricant such as magnesium stearate or sodium lauryl sulphate may enable surface coating of micronized particles. This can improve the flow property of the API, reduce the likelihood of re-agglomeration, and improve the wettability of particles, which in turn increases the API’s dissolution rate. In addition, for inhaled drugs, co-micronization with an excipient carrier such as lactose can improve the aerosolization of highly cohesive drug substances. Co-micronizing with a fine-grade carrier has been reported to give a higher respirable fraction as compared to a coarse grade carrier.13
Micronization can disrupt or activate the crystalline structure of an API and affect the overall crystallinity of the powder, resulting in amorphization of the drug.14 In some instances, this can be desirable for a poorly soluble API. However, this amorphous form tends to revert to a lower energy and a more stable crystalline state upon storage, which can negatively affect the performance of the drug.15 Co-micronization with a polymeric excipient such as polyvinylpyrrolidone can help stabilize this micronization-induced amorphization of the API.16
Summary
As small molecules remain the industry mainstay for the foreseeable future, enabling technologies such as micronization will continue to provide a viable solution to address the formulation challenges of poorly soluble compounds. Beyond bioavailability enhancement, micronization can help develop suspensions, as well as other formulations such as dry powders for inhalation, and improve the content uniformity of HPAPI drug products. In terms of processability and regulatory acceptance, micronization is a well understood, high yield, cost effective processing technology that can be applied in early phase development and be successfully scaled up to commercial production.
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