THE SCIENCE OF SOLUBILITY AND THE SUCCESS OF AMORPHOUS SOLID DISPERSIONS

Citation: Nair R, “The Science of Solubility and the Success of Amorphous Solid Dispersions”. ONdrugDelivery Magazine, Issue 88 (Jul 2018), pp 26-30.

Rashmi Nair discusses the persistent challenge presented by poorly soluble drug formulations in oral drug delivery. Furthermore, she goes on to highlight the promise shown by amorphous solid dispersions, despite the difficulties they present.

INTRODUCTION

Oral drug delivery is generally considered to be the most common route of drug administration, due in large part to the fact that it offers major advantages, such as self-administration, non-invasiveness and cost-effective production. Oral delivery constitutes about half of the total drug dosage forms in use today. In 2017, the US FDA approved 46 drugs, of which 24 were oral dosage forms.1

“Ideally, a holistic plan to evaluate and address bioavailability challenges should be devised at the initial drug development stage…”

As a drug traverses the gut, it encounters various environments, enzymes, pH media, microflora, etc. The drug dissolves, solubilises and then permeates through cellular membranes to impart its action. This seemingly simple process is jeopardised when a drug undergoes first-pass metabolism, does not dissolve or has permeability issues, and such cases are not rare. About 17% of clinical attrition is attributed to pharmacokinetic and bioavailability issues.2

The biopharmaceutical classification system (BCS) was introduced in 1995 and continues to be a reference for preliminary evaluation and categorisation of drugs as soluble, permeable or otherwise. In vitro and in silico tools have added advanced predictability to the drug discovery and development process.3 Yet still the challenge of poorly soluble drugs with bioavailability issues remains under resolved.

One major reason attributable here is the way in which drug development is currently happening. The focus of lead selection and optimisation is to show pharmacological activity at target sites/receptors (biological selectivity and specificity). For this, lipophilic ligands are added to drug structures, which in turn generate highly lipophilic drugs that present challenges of solubility in biological fluids. This problem is usually only identified in late clinical stages, while during preclinical in vivo and in silico testing the early formulations are either solutions in solvents, surfactants, etc, or the issue is masked by a low drug dose.4 To a large extent, enabling formulation interventions can address solubility and bioavailability challenges of drugs.5 Time to evaluate the need for such interventions is critical.

“Any enabling formulation approach needs to distinguish itself as discovery formulation, preclinical formulation or clinical formulation. Until late-stage clinical study, it is preferable to keep the formulation as simple as possible…”

Ideally, a holistic plan to evaluate and address bioavailability challenges should be devised at the initial drug development stage. It is easier to make process changes when the product is in the drug substance development stage than in the drug product. Two examples of processes which could potentially benefit the drug development process are the use of crystallisation models for small size crystals, which could avoid micronisation, or the evaluation of various solid forms, which could help select more soluble forms, such as an amorphous form. “Formulate-ability” can be better assessed if an integrated approach is followed from drug discovery to drug product development.6

THE SCIENCE OF SOLUBILITY

A combination of prognostic and diagnostic tools would be required for assessing the solubility and bioavailability challenges of a drug. One of the first steps is to determine solubility. It is important that the solubility testing is performed in the relevant media, representing the physiological environment that a drug is likely to encounter in vivo. Intrinsic dissolution testing, pH solubility profile and solubility in simulated fluids (gastric, intestinal, etc) can provide valuable information as to whether a drug has a solubility and/or bioavailability challenge and, if so, what the cause may be.

“In recent years there has been a surge in the utilisation of amorphous solid dispersion technology. In spite of the challenges of solid state stability, it is continuing to garner the attention of researchers…”

The possible causes include solvation-limited solubility (grease ball drugs that have high log P/log D values, i.e. >3) and solid state-limited solubility (brick dust drugs that have a high melting point, i.e. >200°C), both of which need to be addressed with enabling formulation strategies.7 Few drugs have characteristics of both classes, i.e. high log P values and high melting point like levothyroxine (log P 4.6 and Tm 235°C) and are therefore difficult to formulate.8 Increasingly the role of in silico tools, in vitro tests and computational predictions have to play is being recognised.9

Bioavailability is an important pharmacokinetic parameter that defines the fraction of drug reaching systemic circulation. Various factors, physiological and physicochemical, affect bioavailability. When devising a strategy for enhancing bioavailability, it is important to identify the reason bioavailability is low in the first place.10 Formulation interventions are better suited to situations where bioavailability is a function of drug’s dissolution and solubility. Permeability modulations, though possible, are not very easy to achieve because of the multiple factors that exert influence in this area.

FORMULATION INTERVENTIONS FOR SOLUBILITY AND BIOAVAILABILITY ENHANCEMENT

As per the BCS, class II and class IV drugs are amenable to formulation interventions for solubility and bioavailability enhancement (Figure 1).11 Selection of appropriate formulation strategy would depend on following considerations:

• Stage of drug development where formulation is required: At the early stages of drug development (preclinical and before), availability of limited drug quantities and constraint of time and money necessitate that a simple, reproducible and physico-chemically stable formulation is developed. From Phase I onwards, a more in-depth study is possible and various formulation strategies could be evaluated. However, if a solubility enhancement is applied at later stages, it calls for a bridging study between the early- and late-phase formulations,12 which would obviously result in additional work and cost.

  

  Figure 1: The BCS system of drug classification.
• Purpose of formulation: It is important to understand the purpose of a formulation development, e.g. a toxicology study requires the maximum exposure of a drug, a Phase I study is for dose ranging, Phase II requires a composition that is closer to the market product, etc. Each phase has clear objectives and a fit-for-purpose formulation should be designed. Accordingly, the approach that is utilised for enabling formulation development needs to be considered.

It would be appropriate at this juncture to state that any enabling formulation approach needs to distinguish itself as discovery formulation,13 preclinical formulation14 or clinical formulation.15 Until late-stage clinical study, it is preferable to keep the formulation as simple as possible, mainly for the following reasons:

• Addition of many additives/excipients would require extensive drug excipient compatibility studies.
• Complex technologies would require a lot of work on the process, its optimisation, scale-up, etc. This would delay the drug to dosing stage.
• Until Phase I/IIa, formulation development is an iterative process which could involve various changes to the target in vivo profile of the drug. Therefore, investing in sophisticated product design/process would not be appropriate.

There are various tools that are utilised to support the decision of which enabling formulation approach should be selected for a poorly water-soluble drug.17 Formulation scientists are moving towards a more structured and predictive model. A few important tools are:

• High throughput screening (HTS) of physicochemical and biological properties
• Mini-scale preparation, in vitro testing and ex vivo studies
• Guidance maps
• Decision trees
• Computer modelling and simulations.

Drug classification systems are also evolving from the BCS to the developability classification system (DCS). The DCS was devised by Butler and Dressman18 and it subdivides class 2 into 2a (dissolution rate limited) and 2b (solubility limited), further guiding the decisions for appropriate enabling formulations.

Thoroughly knowing the drug molecule is the best way to identify and resolve solubility and bioavailability challenge.

AMORPHOUS SOLID DISPERSIONS

In recent years there has been a surge in the utilisation of amorphous solid dispersion (ASD) technology. In spite of the challenges of solid state stability, it is continuing to garner the attention of researchers, a fact which is evident from the success of products that are majorly produced by solvent-based methods (Figure 2) or using hot melt extrusion (Figure 3).

Figure 2: Chronology of product approvals for solvent-based ASDs.

 

Figure 3: Chronology of product approvals for hot melt extrusion-based ASDs.

 

Figure 4: Top ten areas of research in ASDs.

Table 1: Typical analytical testing parameters and methods for ASDs.

CONCLUSION

Most technology-based products add some complexity in development but have the potential to provide enormous benefits in terms of product intellectual property and limited competition. It is worthwhile to assess and utilise technologies like ASDs, which could be used as early as the preclinical phase and eventually transform into commercial products. Regulatory authorities are encouraging well-controlled, process-based products through initiatives supporting continuous manufacturing and application of process analytical technology (PAT) tools.

In the next few years, amorphous solid dispersion technology is likely to see greater technical advancements.

The views and opinions expressed in this article are solely those of the author and are not necessarily shared by Dr Reddy’s Laboratories or any other organisations with which the author is affiliated.

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