Over the past few decades, many small molecules have become more lipophilic or more hydrophobic, which are not necessarily equivalent. More lipophilic molecules are molecules with a higher logP and thus higher lipophilicity. More hydrophobic molecules tend to be those with very strong crystal structures, but not necessarily higher lipophilicity. Their solubility is limited by the necessity to break these crystal structures into individual molecules.
There are a number of reasons why we see more lipophilic and hydrophobic molecules. First, therapies are aimed at more lipophilic biological targets, so by necessity lipophilic molecules need to be designed to interact with those targets to have a physiological effect.
Second, high-throughput synthetic chemistry techniques, such as combinatorial and click chemistry, which are now commonly used, tend to produce molecules with poorer physicochemical properties, with a skew toward very strong crystalline structures and high logP.
Third, several decades ago, when the pharmaceutical industry was still in the early development stages — even as recently as the 1970s — there was a still wealth of compounds exhibiting good physiological effects and physiological efficacy available for consideration as drug candidates. Over time, these types of sweet-spot molecules have become less and less common, this is known as the “low hanging fruit” hypothesis.
Looking into the future at what’s next for orally delivered small molecules, we expect the chemical space to continue evolving toward yet greater complexity. Compounds such as peptides, oligopolymers, and PROTAC molecules, complex bifunctional molecules that trigger cell destruction, are key examples. These types of molecules are even bigger, even more lipophilic, and could well be even more poorly soluble than previous drug candidates, so the shift in this direction will increase in the future.
Oral solid dosage forms are typically capsules or tablets. When a tablet is swallowed (ideally with the recommended 250 milliliters of water, but typically with a small sip), the water and the medication pass from the mouth through the esophagus and into the stomach. The stomach has a low pH of approximately 1.2. If the molecule is soluble at pH 1.2 (typical for basic compounds), it will begin to dissolve in the stomach.
Gastric clearance occurs next and takes place anywhere from 30 minutes to three hours after the tablet enters the stomach. Essentially, the entire contents of the stomach are released into the intestines, which are the main site of absorption for drug molecules.
In order for the drug to be absorbed in the intestines, it must be solubilized in the gastrointestinal fluids, which are more basic than the stomach, with a pH of approximately 6.5, and contain various bile salts and phospholipids. All of these components can contribute to enhanced solubilization.
However, if the drug substance is insoluble or has low solubility in the gastrointestinal fluids, it will not be absorbed through the intestinal membrane. The permeability of the drug substance in the intestines is also important — if the API has a low permeability, then it will also experience low absorption.
PVA-based Parteck® MXP excipient is a pure PVA with optimized particle properties that result in a constant process and flow through the extruder, leading to high reproducibility.
These two parameters — solubility and permeability — are the two key drivers for absorption from the intestine. They are also the two factors upon which the biopharmaceutical classification system (BCS) is based. This system groups drugs based on their solubility and permeability.
BCS class 1 drug substances are both soluble and permeable and thus do not present any bioavailability issues. They reach the intestine, dissolve into solution, and then pass through the intestinal membrane into the circulatory system.
BCS class 2, the most common class, comprises molecules that have poor solubility but good permeability. These drugs dissolve only to a limited degree, but the small amount of API that is dissolved has no problem passing through the membrane. Nevertheless, the low solubility limits the absorption.
BCS class 3 drug substances have the opposite properties: good solubility but low permeability. These APIs readily go into solution but then have difficulty passing through the intestinal membranes, thus also resulting in limited absorption.
BCS class 4 compounds are molecules with both poor solubility and poor permeability. These APIs are the most challenging molecules to be absorbed by the body.
There are two potential explanations for a drug exhibiting low solubility: dissolution limitations or solubility limitations. For solubility-limited compounds, the thermodynamic solubility of the molecule is inherently low. For dissolution-limited compounds, the thermodynamic solubility may be okay, but the rate at which the drug dissolves may be so slow that a low solubility is observed. Each of these two conditions requires a different approach.
For dissolution-limited solubility, this issue can be addressed relatively easily by reducing the particle size via micronization or, in extreme circumstances, nanosizing. Reducing the particle size increases the surface area of the drug exposed to the gastric fluids, resulting in faster dissolution rates, as described by the Noyes–Whitney equation. Poloxamer excipients and other surfactants can also be used to overcome dissolution-limited solubility, making the environment more favorable for dissolution and thus increasing the dissolution speed.
For solubility-limited compounds, the solutions are slightly more complex. The first possibility involves medicinal chemists exploring ways to modify the structure of the molecule, such as adding functional groups that slightly increase the polarity and slightly decrease the lipophilicity of the molecule or conversion into a prodrug with greater solubility that will be broken down in the body after absorption into the active API. Alternatively, the compound could be synthesized as a salt, dependent on the overall pKa of the molecule. More often than not, however, the medicinal chemists have already evaluated these options and found that any structural changes will negatively affect the efficacy of the drug product. Therefore, solubility-limited compounds are often addressed with formulation technologies.
For lipophilic compounds (compounds with high logP), it is often effective to use a lipid vehicle. The API is dissolved in a lipid, and that pre-dissolution allows for enhanced absorption once the drug substance reaches the gastrointestinal tract.
Complexation with cyclodextrin excipients is another option. The API is released from the complex into the solution at a higher rate than it would naturally dissolve, which can drive absorption. For many APIs, however, cyclodextrin complexes have rates of release that are too slow to provide any significant gain in absorption.
A third option is solid-state modification. Many compounds with low solubility have very strong crystal lattices. A crystal lattice is the structure of the intermolecular bonds that hold individual molecules together, and those bonds can be fairly week or very strong. In molecules with strong crystal lattices, molecules cannot go into solution very easily because of the tight bonds holding those molecules together in the crystal lattice, which require energy to be broken. A good example here is salt: at a certain point salt will not dissolve in a cold glass of water, but if the water is heated (i.e., more energy is supplied) then the bonds will be broken, and more salt will dissolve.
In addition to enhanced API solubility and bioavailability, HME also increases the flexibility in drug release properties and is suitable for both immediate- and sustained-release formulations.
We cannot, however, heat up the contents of the gastrointestinal tract. Therefore, the crystal structure of the molecule can be a limiting factor for solubility in the body. What we can do, however, is remove the crystal structure altogether by formulating an alternative solid state. Of most interest for pharmaceutical applications is the amorphous solid state, in which no crystal bonds exist, and thus molecules are essentially loosely associated, making it easier for them to break away and dissolve. From a thermodynamic perspective, the solubility of an amorphous solid is substantially higher than the solubility of a crystalline solid.
The problem is that the amorphous solid state is not a normal thermodynamic equilibrium but a state of very high free energy, which typically results in recrystallization. To access the enhanced solubility offered by the amorphous form, we have to stabilize it.
Two main technologies are used to create amorphous solid dispersions (ASDs). The first involves the formation of a polymer-based matrix within which the drug substance molecules are homogenously dispersed and prevented from recrystallizing. The second method involves mesoporous silica carrier systems in which the highly porous mesoporous silica acts like a sponge, absorbing API molecules into nanoscale pores and again preventing them from bonding to one another in a crystalline form.
To form a solid dispersion using HME, the API is molecularly dispersed in a polymer matrix using elevated temperature and the mechanical force provided by extruder screws (Figure 1). In addition to enhanced API solubility and bioavailability, HME also increases the flexibility in drug release properties and is suitable for both immediate- and sustained-release formulations. In addition, HME facilitates various downstream operations, including direct shaping of the extrudate into tablets, direct tablet compression, pelletizing, and milling.
When developing HME processes, it is possible to test a model compound and screen different polymers to determine which might provide the most stable ASD. Various polymers traditionally used in HME processes include cellulose derivatives, polyacrylates and polymethacrylates, polyethylene glycols, and polyvinyl pyrrolidone (PVP).
All of these polymers are rather inert, with fairly simple structures to avoid radical formation during the HME process. The melt viscosities vary, and choosing a polymer with the right viscosity at the target process temperature is critical, because an appropriate viscosity is essential for achieving a homogenous and reliable process. The quality/grade of the polymer, such as the homogeneity of the particle size, is also important to ensure consistent feeding into the extruder.
PVA is a relatively simple, stable, synthetic thermoplastic polymer particularly well-suited for HME. It has been used in approved drug products for decades and is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA). With the introduction of lower-viscosity PVA grades, it has become useful for HME applications.
Notably, as the shear rate in the extruder increases, the viscosity of PVA drops slightly, which benefits the HME process because the higher the shear forces, the easier the extrusion — including higher throughput, improved downstream processing, optimized melt flow through the channels, and extended process ranges. PVA also provides a very high batch consistency.
PVA-based Parteck® MXP excipient was specifically developed for use in HME. It is a pure PVA with optimized particle properties that result in a constant process and flow through the extruder, leading to high reproducibility. PVA is produced by the hydrolysis of polyvinyl acetate, and, for Parteck® MXP excipient, 88% of the ester groups are hydrolyzed, leaving 12% of the acetate groups.
Parteck® MXP exhibits amphiphilicity during the HME process that is not typically observed with other polymers. This is advantageous with respect to enhancing the flow of the generated ASDs and increasing and maintaining supersaturation during drug release for a longer time period. That is a clear advantage that you don’t see in common polymers. Parteck® MXP also has a lower melt viscosity, which enables optimized melt flow behavior during the extrusion process.
ASDs release the API at a higher dissolution rate than would occur naturally, leading to concentrations that are substantially higher than the thermodynamic solubility, or supersaturation. Because more API is dissolved than would be possible under normal conditions, the supersaturated state is an unstable or meta-stable state. The system possesses a high amount of excess energy that it wants to be rid of, which is achieved by precipitating the API out of the solution.
With ASDs, therefore, the goal after achieving supersaturation in the gastrointestinal tract is to inhibit precipitation and maintain that supersaturation long enough to allow absorption. In HME formulations, Parteck® MXP does just that — it prevents APIs from precipitating out of solution. Altogether, this approach is referred to as the “spring and parachute” model of formulation. In this model, Parteck® MXP is able to act as both spring and parachute, by stabilizing and delivering the amorphous API and then preventing precipitation from the supersaturated state.
Good precipitation inhibition is achieved through certain interactions that occur between the drug and the PVA (or other) polymer in solution. A polymer cannot be too hydrophobic, or it will not interact with water molecules, and the API will precipitate. On the other hand, the polymer cannot be too hydrophilic, because then it won’t interact with the drug molecule.
With Parteck® MXP, we have developed a grade of PVA with the right balance of hydrophilicity and hydrophobicity. It interacts with water and also rotates to form unique conformational structures that allow it to also interact with APIs, thus keeping them in solution. These interactions are illustrated in Figure 2.
Specifically, in addition to the hydroxyl groups of the PVA interacting with the water and the API, stabilization is also achieved through interactions between the lipophilic components of the API and the backbone of the PVA. In the example shown in Figure 2, the aromatic structures of the API interact with the PVA backbone.
In addition, PVA is stable up to 250 °C, which is much higher than other commonly used HME polymers, and extends the normal operating range of hot melt extrusion.
As a business unit, we aim to tackle the biggest challenges in solid formulation. The first challenge is solubility, which we continue to address. Low solubility remains a big challenge, and we particularly look forward to helping customers overcome issues presented by more complex novel modalities in the oral solid dosage form space.
The second challenge relates to enabling evolving manufacturing techniques. We already see the rise of continuous solid dosage form manufacturing and are actively developing products to facilitate that shift by our customers.
While it is hard to predict what will happen in the future, MilliporeSigma is continuously working on the formulation challenges that face our customers and the industry as a whole.
The third challenge is additive manufacturing. 3D printing is already an established pharmaceutical manufacturing technique, and we expect it to become even more prevalent in the future. In the near term, it will enhance the efficiency of early development through rapid prototyping and more streamlined clinical trial supply. Further into the future, it will become an essential enabler of precision and personalized medicine.
The final challenge involves digitization of formulation to enable more predictive capabilities. We are committed to this goal and are already working on solutions to achieve it.
As we develop new products, we gain a greater understanding of the challenges our customers face and more experience with process optimization. We are then able to share information about our new products as well as tips for how to implement processes more effectively.
We know that HME is a new and still emerging technology of interest to many companies. These companies want to move into HME but need support in the early stages to set up the equipment and establish the right parameters. MilliporeSigma is committed to providing advice and support to customers during this introductory phase and formulation development.
From our perspective, the great advantage or differentiator of MilliporeSigma is our diversity. We are a company that has many experts in various technology fields relevant to the pharmaceutical industry, including those that are not always readily apparent. All of these experts from different fields working closely together really enhance our development capabilities because we can access input from many different sides and angles.
We see no reason to expect that drugs will stop being poorly soluble. On the contrary, we expect that, with new chemistry emerging in the solid space, such as protein interaction inhibitors and PROTAC molecules, the physical chemical landscape is going to become even more difficult. As a result, current solutions may not meet the demands of the future, which is why we are working on those solutions already today.
While it is hard to predict what will happen in the future, MilliporeSigma is continuously working on the formulation challenges that face our customers and the industry as a whole.
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