Issue:October 2020

OSD FORMULATIONS - Dissolving Bioavailability & Solubility Challenges in Formulation & Development


An increasing number of highly potent and complex small molecule formulations are entering development pipelines. A preferred dose form, oral solid dose (OSD) formulations, continue to lead drug research, development, and approvals – 2019 saw the highest percentage of OSD approvals since 2013.

According to the US FDA Center for Drug Evaluation and Research (CDER), of the 38 small molecule drugs approved by the agency in 2019, 26 (68%) were OSDs (19 tablets and 7 capsules). Notably, one New Molecular Entity (NME) was approved both for oral and parenteral delivery.

Many of the innovative and novel formulations introduced by the pharma industry throughout the past decade have had to cope with poorly water-soluble active pharmaceutical ingredients (APIs). Considering the pace of development, overcoming solubility issues will remain problematic. This is especially true for important new classes of pharmaceuticals entering the market.

Poorly water-soluble API chemistries require much more than a neutral excipient to deliver the dose. Overcoming bioavailability and solubility issues can bog down development and slow commercialization timelines because formulators often face a cascading set of complexities trying to deliver their API payloads with accuracy. Facing down insolubility issues requires a comprehensive understanding of the physiological pharmacokinetic and pharmacodynamic processes that happen between swallowing the dose and its uptake in vitro.

Overcoming bioavailability and solubility issues can slow commercialization timelines because formulators often face a cascading set of complexities trying to deliver their API payloads with accuracy.


Innovation in combinatorial chemistry and other recent advances in pharmaceutical and biopharmaceutical science are leading to exciting new discoveries and patient breakthroughs. Although APIs in these drug products may ultimately offer extremely good therapeutic performance, if they cannot enter the bloodstream efficiently from an orally administered solid dose, overall drug strategy can be compromised.

It’s extremely challenging because formulators face a broad range of compromises they might not want for their drug because of patient and standard-of-care terms – for example, not surrendering the formulation to parenteral delivery for the sake of patient convenience and dose compliance.

Enhancement of dissolution, solubility, and bioavailability for poorly soluble APIs can be achieved using a number of different approaches, including particle size reduction (eg, micronization and nanomilling), salt or cocrystal formation, lipid-based self-emulsification, and the formation of amorphous solids dispersions (ASDs).

Regardless, many new compounds and chemistries have either low solubility or low bioavailability or both. As such, they present unique challenges to formulators depending on their drug delivery strategies.


To assist therapeutic performance, there are generally two ways to increase solubility: 1) a chemical modification approach or 2) a formulation approach. Chemical modifications include either taking a pro-drug approach or employing a salt form of the drug. Most formulators understand there are increasing degrees of complexity involved in using a salt form to increase solubility due to the need to develop salt form synthesis and purification methods.

That’s why formulation methods, such as micronization, amorphous solid dispersions, nanocrystals, and nanoparticularization techniques, are increasingly popular in the field of solubility enhancement.

To increase solubility of APIs, two common approaches - chemical modification or formulation are available. Chemical approaches have proven utility, but formulation methods, including micronization, amorphous solid dispersions, nanocrystals, and nanoparticularization, are becoming increasingly popular to support therapeutic performance.


Two principles are being used to produce nanoparticles: top-down approaches like milling or ultra-homogenization, and bottom-up approaches including precipitation. Micronization is a simple approach, in which the particle size of the API is reduced, leading to higher particle surface area and eventually better solubility performance. Although these concepts have shown positive results for many drugs, there are some APIs that need further formulation techniques to increase solubility.


Nanocrystalization is an emerging technology that is helping formulators deal with the challenges of improving the solubility and bioavailability of their poorly soluble APIs. Nanocrystals will account for 60% of a $136-billion nanotechnology-enabled drug delivery market by 2021.1

Essentially, crystalline particles range in size from 2 nm to 1,000 nm. Nanocrystals are ground in special mills, and the procedure enhances the surface-to-volume ratio and thus, the solubility and bioavailability of most insoluble pharmaceuticals. Due to crystalline characteristics, they offer better stability compared to their amorphous counterparts. In addition to bead milling, nanocrystals can be prepared by high-pressure homogenization and precipitation.


Nanocrystals work to improve solubility through an increase in surface area beyond that provided by just micronization. This is especially helpful in improving solubility of drugs in which it is limited by dissolution rate. Amorphous nanoparticles are even more advantageous in improving solubility, but they come with the challenge of requiring stability to prevent conversion to the crystalline forms.

Another characteristic of nanocrystals that supports therapeutic performance is the fact that particles are 100% API and require no excipients.

Due to crystalline characteristics, they offer better stability compared to their amorphous counterparts and can be administered as dispersions in the liquid medium or in the solid state.

Nanocrystals can also be prepared by bead milling, high-pressure homogenization, and precipitation. One of the main advantages of this technology is it allows for higher API drug loads per dose. However, this process requires surfactants as stabilizers, which may prompt new formulation complexities or other negative effects.

To increase solubility of APIs, two common approaches - chemical modification or formulation are available. Chemical approaches have proven utility, but formulation methods, including micronization, amorphous solid dispersions, nanocrystals, and nanoparticularization, are becoming increasingly popular to support therapeutic performance.


Apart from these methods, target-specific and site-specific drug delivery is gaining renewed momentum among pharmaceutical developers. Nanoparticulate methods and technologies being employed now are well understood and offer developers broad utility and fewer compromises when it comes to managing optimal dose delivery.

For example, many developers are turning to enteric-coated multiparticulate systems in tablets and capsules. This technology is demonstrating great utility and functionality particularly for acid-sensitive drugs.

Nanoparticulate technology is transforming the industry’s ability to successfully formulate poorly soluble APIs. Nanoparticulate formulations of poorly dissolving APIs can provide faster drug absorption and higher bioavailability by increasing dissolution rate.

When it comes to developing challenging compounds, it helps if the scientists know whether the client has performed preliminary solubility studies, any kind of simple animal PK studies, or even what the critical quality attributes are, such as modified release or the need to deliver the drug in the small intestine.


A Metrics client had an API susceptible to acid degradation and general hydrolysis, which meant it had to be protected from stomach acid. In addition, exposure time to fluid in the small intestine needed to be minimal.

Following analysis, it became apparent an enteric coating was needed to provide acid protection. As a second line of defense, chemists incorporated muco-adhesive polymers into the core tablet, to help it adhere to the walls of the small intestine.

This allowed the actives to permeate across the small intestine, where it then was hydrolyzed to the API. Despite the challenge of preventing hydrolysis throughout transit in the stomach and small intestine, animal studies confirmed that it provided bioavailability of the molecule of interest.


Many APIs available today are crystalline in nature and exhibit poor solubility. However, crystalline APIs can be converted into amorphous particle forms, shaped to offer more surface area. Generating ASDs is well understood and accomplished commercially using spray-drying technologies.

Preparing an API into an amorphous form rather than a crystalline state can support desired dissolution profiles and enhanced bioavailability. However, because amorphous compounds are thermodynamically less stable, it is often necessary to employ polymeric matrices to improve their stability.

Once ASDs reach the GI tract, the API is released in concentration. According to one study, more than 80% of amorphous dispersions offer improved dissolution rates and bioavailability.2


Amorphous dispersions offer drug formulators the ability to deliver an OSD final drug product in the form of a tablet or a capsule. ASDs allow the formulation of drug products with much higher dosage levels compared to lipid-based systems. Ultimately, these formulations allow for more API in a single dose, and that means more medication in fewer doses for patients.


A Metrics Contract Services client needed support for a commercialized drug product indicated for curative treatment. The intellectual property owner was hoping to develop a second-generation formulation for a clinical trial studying the drug’s efficacy as a preventive treatment. The clinical trial expected to enroll patients for whom medication compliance was a primary issue and could impact dose compliance. Thus, the client hoped to encourage patient compliance with an easy manageable “one-and-done” daily dosing.

The developer’s second-generation iteration required almost every deliverable a formulation development scientist could imagine — uniform-sized multi-particulate for consistent controlled release; taste-masking and a smaller particle size to improve patient compliance; not to mention a 24-hour modified release for once-a-day dosing; and dose dumping prevention.


This situation was a first for Metrics senior formulation scientists. Never had they encountered a project with so many formulation development deliverables. With most projects, Metrics commercial partners choose two or three deliverables that are most important. But this clinical trial would involve unique patients who could easily fail to carry out a medicine regimen, so compliance was critical and challenging.

The Metrics team established critical quality attributes that were achievable for the product — the most important attribute being controlled release for 12 to 24 hours. The API’s highly water-soluble nature posed significant challenges to achieve any kind of controlled release.

Controlled release was achieved by layering the drug onto a substrate and then applying a completely insoluble functional coat using a solvent-based coating system. The downside of achieving the controlled release was the large amount of drug product needed to achieve a therapeutic dose concentration of 25% to 35% w/w.

However, Metrics was able to increase the drug concentration by making pellets of the drug through extrusion and spheronization. The next steps for this complex dosage form were to increase patient compliance through taste-masking and making a suspension of the pellets.


The team created a highly water-soluble compound in a dosage form with controlled release. Despite using a completely insoluble coating, the team was able to push API out from the center of the beads. The functional coat consisted of completely insoluble material (ethyl cellulose and dibutyl sebacate as the plasticizer) and yet drug product still released from the core. Metrics found that using a solvent system, as opposed to an aqueous dispersion and cure times, gave a nice, contiguous coat that could provide the desired controlled release.

The client used the formulation to successfully conduct a Phase 1 clinical trial. The company is proceeding to Phase 2 clinical trials leveraging the same formulation process Metrics developed using a different starting substrate.


Many pharmaceutical analysis tools are used to characterize a drug product, but dissolution testing plays an important role in defining the performance of a drug ensuring product quality.

There are many reasons why dissolution testing is so important. Dissolution testing is the only pharmaceutical tool that can assess both drug product performance and adherence to key quality attributes based on the design of the drug. From simple immediate-release formulations to complex modified-release formulations, an accurately developed dissolution method is critical for confirming product quality over time and under various conditions.

If an in-vitro dissolution testing procedure shows significant correlation with in-vivo clinical data, it can provide predictive modeling that may eliminate the need for additional clinical studies over the product’s lifetime. Not only can dissolution provide valuable predictive modeling, it can also help resolve unexpected bioavailability results.

Biorelevant dissolution media is ready to bridge the gap between a quality control procedure and predictive modeling as a measure of pharmacological clinical relevance. Dissolution testing also provides support for formulation development and prototype selection — either during early phase development or in support of post-approval changes.

While stability indication of an assay and the impurities procedure is scrutinized during Chemistry, Manufacturing, and Controls (CMC) review, dissolution data helps gain the focus to ensure the optimal procedure is developed.

Indeed, many regulatory guidance documents have been published requiring a gradual progression of dissolution throughout the phases of drug development or in support of Scale-Up and Post-Approval Changes (SUPAC) requirements.


For drug developers and their commercial drug product manufacturing partners, there is likely no “last word” regarding improving the solubility of today’s prominent APIs. Although innovation is introducing new challenges, lifecycle management and new marketing strategies are also prompting developers to dissolve the solubility issues of existing products. Ultimately, the effort and investment will continue as pharma seeks to deliver improved products to patients.



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Dr. Vinod Patil is Manager, Pharmaceutical Development at Metrics Contract Services, directing a team of formulation scientists and specialists who develop novel oral solid-dose formulations for Phase 1 through Phase 3 clinical trials, and then scale-up and support of the validation and commercialization of those products. He provides technical leadership and oversees GMP compliance on a variety of ongoing formulation and process development projects. He assists in budget planning and works with client services on service estimate generation, assignment deadlines, and other matters related to new business development. Dr. Patil earned his BS in Chemical Engineering from the Institute of Chemical Technology in Mumbai, India and his PhD in Chemical Engineering from the University of Kentucky.