Poor Solubility – Where Do We Stand 25 Years after the ‘Rule of Five’?

[Note: This paper is based on a Prologue presentation given by the author at AAPS PharmSci360 of the same title broadcast via the web on October 28, 2020.]

Summary

It is clear that medicinal chemists have moved beyond the ‘Rule of Five’ paradigm. With the advent of combinatorial chemistry and high throughput screening, there has been an increase in the number of poorly water-soluble drug development candidates. The different methods for enhancing dissolution and bioavailability of such drug candidates have been reviewed. Methods are available for the formulation of most small molecule poorly water-soluble drugs as immediate release oral solid dosage forms. Identification of the optimum bioavailability enhancement method will depend on the properties of the drug molecule, the dose and the target patient population. The formulation scientist has to balance the advantages and disadvantages of the different formulation technologies as they apply to the particular drug development project. The choice of dissolution method will also be important.

Introduction

The ‘Rule of Five’ (Ro5) is clearly aimed at medicinal chemists.^1,2

However, in the past 25 years we have seen an increase in the number of poorly water-soluble drug candidates, to the extent that as many as 70 – 80% of small molecule drug candidates may be classified as poorly water-soluble today. This paper will review Ro5 from a formulation scientist’s perspective, and discuss methods used in the formulation of poorly water-soluble drugs as immediate release oral solid dosage forms.

Poor Water-Solubility

What is meant by ‘poorly water-soluble’? In the regulatory literature, such as FDA Guidance documents, there is no official definition of poor water-solubility. The Biopharmaceutical Classification System (BCS) and other similar classification systems, classify drugs as either high solubility or low solubility:³

A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media within the pH range of 1 - 6.8 at 37 ± 1°C.

Under this definition, if the drug is not highly soluble, then it is of low solubility. This is an either/or classification and, while relevant, is of limited use in the formulation of poorly water-soluble drug molecules.

This author’s own classification of solubility is a little different, and may be more useful from a formulation scientist’s perspective:

• Soluble: >10 mg/mL over the physiological pH range.
• Poorly soluble: < 1 mg/mL over the physiological pH range.

There is an intermediate solubility range; 1 mg/mL<x<10 mg/mL, to indicate that there is not a fixed boundary, but a gradual transition. For such drugs, dose may be important, and some form of dissolution enhancement may be required which becomes more necessary as solubility decreases.

Poorly water-soluble drugs are not new, and were not new in 1995. Digoxin was first isolated in about 1930 and is poorly water soluble. Griseofulvin was first discovered in 1939, and the effects of particle size on the efficacy of Griseofulvin were established in the 1950s. There were also synthetic steroid drugs which were known to be poorly water-soluble.

In the 1970s, perhaps 5 – 10 % of new drug candidates were poorly water-soluble. In those days, drug candidate screening was based on isolated tissue or whole animal models. These screening models could not cope with poorly water-soluble compounds and they failed in screening. With today’s combinatorial chemistry and high-throughput screening we have the ability to synthesize more compounds and optimize drug-receptor binding to achieve better selectivity, and better binding of the drug to the receptor. Typically, more hydrophobic domains are ‘bolted’ on to the molecular scaffold leading to increased molecular weight and increased hydrophobicity. These both contribute to reduced aqueous solubility.

Rule of Five

Ro5 may be summarized as follows:²

Poor [oral] absorption and/or permeation are more likely when:

• There are more than 5 H-bond donors (expressed as the sum of–OH groups and –NH groups);
• The MWT is over 500;
• The Log P > 5 (or MLogP > 4.15);
• There are more than 10 H-bond acceptors (expressed as the sum of ‘N’s and ‘O’s)

Compound classes that are substrates for biological transporters are exceptions to the rule.

As stated earlier, Ro5 is aimed at medicinal chemists.² For a formulation scientist’s perspective, Ro5 has limitations. Ro5 does not:

• Predict oral absorption or bioavailability
• Give an indication of the formulation approaches that are most likely to succeed with a given drug candidate

For the formulation scientist, Ro5 may give an indication of the likely complexity of the formulation design and development program. Today, the pharmaceutical industry frequently operates in the small molecule space beyond Ro5. Several poorly water-soluble drugs with a mol. wt. >500 Da are commercially available as oral solid dosage forms (see Table 1). Thus, for the formulation scientist, Ro5 is not fool-proof. Also, there are many drug molecules with molecular weights <500 Da that are poorly water-soluble and less straightforward to formulate.

Methods to Overcome Poor Water-Solubility

One method to overcome poor water-solubility is prodrug development. The drug would be modified to improve water-solubility and oral absorption. After absorption from the gastro-intestinal tract, the prodrug moiety would be cleaved thereby providing the drug in the body. There are disadvantages to this approach. The prodrug is a new molecule and there will necessarily be further safety studies required. The synthetic route will need to be modified, possibly complete re-designed. There will also need to be stability assessments, and the like to determine if the approach is viable. These extra studies will inevitably lead to a project delay.

There are formulation options for poorly water-soluble drugs. Dissolution may be described mathematically by the Nernst-Brunner equation:

From Equation (1) we can see that we have three options to increase the dissolution rate:

• Increase the effective surface area for dissolution (A)
• Increase the concentration gradient (C_S – C)
• Reduce the thickness of the boundary layer (h)

Reducing the thickness of the boundary layer is not an option in vivo, and we are left with: increasing the effective surface area for dissolution, or increasing the concentration gradient. It is also possible to combine both approaches; particle size reduction and some form of solubilization.⁴

We can increase the surface area by reducing the particle size of the bulk drug and there are several methods available:

• Milling
• Micronization
• Nano-milling (e.g. microfluidization)
• Nano-precipitation/crystallization

The milling, micronization and nano-milling methods start with large particles and break them into increasingly smaller pieces. These methods are inefficient since most of the energy input into the system is used to generate sound and heat rather than particle size reduction.

Fine particles are generally cohesive, and agglomerate readily. They are also adhesive and often electrostatically changed, both of which makes handling them difficult. In fact, nano-milling is carried out in a liquid suspension to avoid such powder handling problems. In nano-precipitation/crystallization, we start with the drug in solution and add an anti-solvent to cause the drug to either precipitate or crystallize as nano-sized particles which have to be stabilized against agglomeration and recrystallization. Methods using super-critical CO₂ have also been described.

There is a further phenomenon which manifests with nano particles. This can be described by reference to the Ostwald-Freundlich-Kelvin equation:

From Equation (2), we can see that solubility is inversely proportional to the particle radius (r). However, this only starts to become important when the particle radius is reduced below 1 – 2 μm and particularly below ca. 200 nm, i.e. well into the nano size range.⁵ Examples of drugs where a reduction in particle size has been shown to increase bioavailability are included in Table 1.

There are several ways in which we can increase the concentration gradient, including:

• Alternate salt forms
• Metastable crystalline polymorphic forms
• Amorphous forms prepared by e.g.:
  • Spray drying
  • Hot-melt extrusion
  • Co-precipitation
• Nano-precipitation/crystallization (as mentioned above)
• Co-crystallization
• Complex formation
• Co-solvents:
  • Liquid solutions
  • Solid solutions
• Solubilization by surface active agents.

All these methods have been reported in the literature (see for example ⁷). Examples of drug formulated as amorphous forms are presented in Table 2.

There are also other methods by which poorly water-soluble drugs can be formulated. We have known for some time that administration of an oral dose with a high-fat meal increases the bioavailability of some poorly water-soluble drugs. This is believed due to the drug partitioning into the fat portion of the meal and the subsequent formation of a fat emulsion which enables the drug to be better absorbed from the gastro-intestinal tract. This enhanced understanding of fat digestion and absorption has led to:

• Self-emulsifying drug delivery systems (SEDDSs)
• Self-microemulsifying drug delivery systems (SMEDDSs)
• Self-nanoemulsifying drug delivery systems (SNEDDSs)
• Solid lipid nanoparticles (SLNs)

The difference between SEDDSs and SNEDDSs is simply in the particle size of the fat droplets formed. A SEDDS formulation will form a comparatively coarse emulsion with droplets in the μm size range, whereas a SNEDDS will from an emulsion with fat droplets in the nm size range. Thus, SEDDSs and SNEDDSs are true emulsions with a dispersed phase consisting of fat droplets. By contrast, a microemulsion is not a true emulsion, but a ‘single thermodynamically stable phase consisting of lipophilic domains separated from aqueous domains by an intervening surfactant layer’.⁹ Microemulsions typically contain an aqueous phase, an oily phase, a surfactant and a co-surfactant.

Several commercially available drugs have been formulated as self-emulsified systems as shown in Table 3.

Ciclosporin was originally launched as a SEDDS (Sandimmun^®). However, it was eventually reformulated as a SMEDDS (Neoral^®).

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This reformulation resulted in a significant increase in ciclosporin bioavailability.¹⁰

Solid lipid nanoparticles may be formed by several methods, including:⁹

• Hot-melt homogenization wherein the drug-lipid melt is emulsified and cooled.
• Cold-melt homogenization wherein the drug-lipid melt is solidified, ground in a mill, dispersed and then emulsified.
• Solvent emulsification wherein the drug and lipid are dissolved in a suitable lipophilic solvent, emulsified and the solvent evaporated.

Choosing the Most Appropriate Technology

As we can see from the synopsis above, there are several ways we can formulate poorly water-soluble drugs. But, how can we decide which is (are) best for a particular drug? It is not easy to answer this question as there many factors which influence our final choice, including:

• Properties of drug molecule
• Dose
• Target patient population
• Packaging
• Economics

For an innovator drug molecule, its properties will be determined during reformulation screening. For a generic drug, the preformulation information may be in the literature; however, this may need to be supplemented by further studies tailored to the type of formulation method(s) being considered. Preformulation is the foundation for all formulation projects. With poorly water-soluble drugs in particular, if the preformulation investigations are not carried out properly, there is every chance that the formulation will fail. A preformulation assessment for an innovator drug should include at least the following:

• pH solubility profile over the physiological pH range.
• Solubility in biorelevant media (e.g. FaSSGF,¹¹ FeSSGF,¹² FaSSIF¹² and FeSSIF¹² media)
• Solubility in non-aqueous solvents:
  • Polyethylene glycols (PEGs) and other hydrophilic excipients
  • Fats and oils
• Bi-directional Caco-2 monolayer permeability ratio [Note: A full preformulation screen will include the evaluation of other characteristics of the drug molecule: this list includes those properties which, in the author’s experience, are important for an initial assessment of the likely formulation approach(es).]

The pH solubility profile will give information that will be relevant to the BCS classification of the drug molecule. Solubility in non-aqueous media can give information relevant to potential formulation options. PEGs can act as co-solvents and enhance bioavailability of some poorly water-soluble drugs. If the drug is soluble in e.g. vegetable oils such as corn oil, some form of self-emulsifying formulation may be appropriate. It is also important to remember that for self-emulsifying systems, it is necessary to get the drug into solution in the oil/surfactant mixture.

Bi-directional Caco-2 permeability studies give information on whether, or not, the drug will be absorbed from the gastro-intestinal tract, and is relevant to the BCS assessment of the drug. They may also give information as to whether the drug may be subject to efflux ((B→A)/(A→B) > 3) or if there is facilitated transport ((A→B)/(B→A) > 3) where A refers to the apical side and B the basal side of the Caco- 2 monolayer, A→B refers to the apical to basal permeability, etc. If the drug is subject to efflux, the possibility of drug-drug interactions and/or drug excipient interactions must be considered. There is the possibility of co-administration of an excipient which inhibits the efflux mechanism, such as certain non-ionic surfactants. [13] However, the release of the drug and the efflux inhibitor would need to be coordinated in some way.

The dose of the drug will always be important. However, from a formulation perspective high dose drugs are likely to be more difficult to formulate, and some bioavailability enhancement technologies may not allow for a dosage form and/or dosing schedule acceptable to the patient.

The target patient population will also be important. Some types of oral solid dosage form may not be acceptable to certain patients. For example, small children would not be able to cope with large tablets or capsules. Geriatric patients may also have problems with certain types of product. High doses of surfactant and polyols can lead to increased gastro-intestinal motility which may be a problem if the drug is only absorbed in a specific region of the small intestine.

Stability of the final dosage form is always important. We are all aware of the necessity to protect the drug product from chemical degradation. But, with many bioavailability enhancement technologies, the physical stability is just as important for finished product performance. For example, amorphous materials are metastable; exposure to moisture may induce crystallization. In addition, chemical degradation can be accelerated, e.g. hydrolysis or oxidation. This may require extra precautions during manufacture and in the finished pack.

The manufacturing cost of the finished product will also be a consideration. The longer the processing and the more unit operations necessary to manufacture the product, the higher the cost. Similarly, the rate of manufacture will influence costs since a slower rate of manufacture will increase the time necessary for manufacture and thus the cost. In addition, some bioavailability enhancement technologies may require special packaging, e.g., desiccants, oxygen absorbers and oxygen-impervious containers and closures.

The Importance of Drug Agglomerate Particle Size

From Equation (1), one of the ways to enhance dissolution was to increase the effective surface area of the drug. It is important to understand what we mean by ‘effective surface area’. Micronized powders tend to be cohesive. The agglomerates thus formed can be difficult to break down during drug product manufacturing. The ‘effective surface area’ is simply the surface area of the drug in the dosage form as it is presented to the fluids in the gastro-intestinal tract, i.e. the outer surface area (envelop surface area) of the drug agglomerates in the product.

By way of an example of the importance of ‘effective surface area’, consider digoxin. Digoxin is a low dose drug with poor water solubility and a narrow therapeutic range. In the early 1970s in the United Kingdom, patients who had been stabilized on digoxin were presenting in hospital emergency departments with symptoms of digoxin poisoning.¹⁴ The variation in the bioavailability of one brand was ascribed to a change to the manufacturing process that was not thought important at the time. The change caused a considerable increase in the bioavailability of the particular digoxin brand, suggesting a more effective breakup of the agglomerates during processing, thus markedly increasing the effective surface area of the digoxin.

The Importance of the Correct Dissolution Test for Product Release

For most oral solid dosage forms, a dissolution test is required for product release to ensure lot to lot uniformity. For soluble drugs, dissolution in 0.1M HCl using a rotating basket (USP-NF Type 1) or rotating paddle (USP-NF Type II) apparatus is usually sufficient. For poorly water-soluble drugs, the choice of dissolution method is more critical since we want to identify which batches which will not perform as required after administration to the patient. Thus, a dissolution method which predicts in-use performance would be advantageous. However, a full in vitro in vivo correlation (IVIVC) may not be necessary (and may not be possible for an immediate release product). A method which is able to distinguish between drug product lots that give adequate bioavailability, and those that do not, is all that is needed.

Conclusion

The Ro5 was an important step forward for medicinal chemists. However, the use of combinatorial chemistry and high-throughput screening means that medicinal chemists are moving/have moved beyond the Ro5 paradigm. Poorly water-soluble drugs are more common today than they were 40 – 50 years ago. We have drug delivery technologies which allow formulation of most poorly water-soluble small molecule drugs. However, all the methodologies available have advantages and disadvantages and it may not be easy to select the best technology for a particular drug candidate. The formulation scientist must balance the advantages and disadvantages of the different bioavailability enhancement technologies as they relate to their particular project to determine the optimum formulation approach. The choice of dissolution method for QC release testing for poorly water-soluble drug products requires careful consideration.

References

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