Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

	In recent news, it was announced that after several years of clashing over pricing, National Health Service (NHS) England and Vertex have finally struck a deal, which will give patients in England access to treatments for cystic fibrosis, Orkambi, Symkevi, and Kalydeco (1). The definitive agreement covers three medicines from Vertex that are licensed in the United Kingdom for the treatment of cystic fibrosis.

	For cystic fibrosis sufferers in the UK, a country that has the second highest prevalence of cystic fibrosis in the world, it has been a four-year long wait to gain access to Vertex’s Orkambi treatment, which gained European approval in 2015 (2). Orkambi (lumacaftor/ivacaftor) is the first medicine to treat the underlying causes of cystic fibrosis with certain mutations rather than the disease symptoms and complications.

	The back and forth that occurred between Vertex and NHS England is somewhat unusual in that both sides were in a stalemate for a long period of time, using the disagreement over pricing as a defence of one position or the other. For Vertex, which had gained a deal for its Kalydeco treatment worth £400 million over a five-year period in 2013, the pushback from NHS England and National Institute for Health and Care Excellence (NICE) over pricing was not necessarily anticipated. The company refused the pricing offer of £500 million for five-years for Orkambi and other drugs in Vertex’s pipeline-the largest expenditure ever offered by the NHS-which was made public by NHS England, despite all other discussions being confidential. For NHS England, the pricing being demanded by Vertex for Orkambi was deemed to be unaffordable.

	Questions over how treatments are assessed, namely the single technology appraisal system of NICE, were raised as a result of rare disease treatment prices being specified as ‘unaffordable’. In Vertex’s case, the company specified that special considerations to patient population sizes should be factored in when performing appraisals (3). 

	With Vertex and NHS England at an impasse, tensions were frayed and inflammatory remarks and bravado on both sides ensued. As campaigners persisted in their efforts to gain access to Vertex’s treatments, the UK government was called upon to break the deadlock on pricing, even with some calls for the government to invoke ‘Crown Use’, which would have enabled third parties to access intellectual property of Vertex for the creation of generic versions of the medicine, Orkambi (4).

	The potential ramifications of Crown Use were not lost on Vertex, which announced its reaction in a statement, according to the BBC (5). “To invoke Crown Use and provide third parties access to Vertex’s intellectual property would seriously undermine our ability to achieve these goals and would significantly weaken incentives for future innovation,” the statement read.

	An agreement has now finally been achieved, however, and despite exact pricing for the treatment being unknown publically, it has been hypothesized that it is an amount ‘significantly less than the sum originally asked for’ (5). As a result of the agreement, an important and vast market has ultimately now been penetrated by Vertex, adding to markets in Spain, Australia, and Scotland.

	“The UK has the second highest prevalence of cystic fibrosis of any country in the world, so today is an important and long hoped for moment for children and adults living with cystic fibrosis,” said Simon Stevens, NHS chief executive (1). “That fact also means that any drug company wanting to succeed commercially in this field needs to work constructively with the NHS. I’m pleased that Vertex has now agreed a deal that is good for our patients and fair to British taxpayers.”

	1. NHS England, “NHS England Concludes Wide-Ranging Deal for Cystic Fibrosis Drugs,” 

, 24 Oct. 2019.
	2. Vertex, “Vertex Receives EU Approval for Orkambi (lumacaftor/ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis in People Ages 12 and Older with Two Copies of the F508del Mutation,” 

, Press Release, 20 Nov. 2015.
	3. Parliament UK, “Documents from Vertex Pharmaceuticals,” 

, 30 Nov. 2018.
	4. Bill Wiggin, “Bill Wiggin MP Calls for Crown Use License Debate,” 

, Media Release, 31 Jan. 2019.
	5. Nick Triggle, “Cystic Fibrosis Drug Given Green Light in England,” 


	Vol. 31, No. 11
	November 2019
	Page: 6

	When referring to this article, please cite it as F. Thomas, “Striking a Landmark Deal,” 

Articles

After years of discussions around pricing, UK governmental bodies and Vertex have finally reached an agreement on cystic fibrosis treatments.


Striking a Landmark Deal

Avoiding bad or bitter tasting finished drug products is widely accepted as a way of improving patient adherence and compliance to a therapeutic regimen, particularly when considering pediatric and geriatric populations. Many APIs in development, however, are classified as bitter compounds.

	Elaborating on this point, Krizia M. Karry, global technical marketing manager, BASF Pharma Solutions, highlights a study by Dagan-Wiener 

which revealed that two-thirds of current clinical and experimental drugs were classified as bitter (1). “Aversion to bitterness, or in general, product palatability, has been demonstrated to affect treatment completion,” she says. “For example, in 2007 the average treatment completion rate of pediatric patients was only 58% with palatability and formulation being attributed as major contributing factors. To this day, this has not changed.”

	In agreement, David Tisi, director of operations, Senopsys, adds that on top of bitterness, many active ingredients have other undesirable sensory attributes, such as smell or trigeminal irritation. “Furthermore, excipients used to increase drug solubility or used for preservation are known to create or exacerbate the taste masking challenge,” he notes.

performed a series of experiments assessing taste the perception of bitter or sour (2). In the experiments, it was realized that confusion between sour and bitter tastes existed in the general population. For Tisi, the difficulties in determining how a patient perceives the taste of an ingredient is a major challenge that must be overcome by the formulator. “Untrained healthy volunteers often describe drugs as ‘bad’ or ‘yucky’ tasting, which is not very helpful as there’s no ‘good’ or ‘yummy’ ingredient on the shelf to improve palatability,” he says.

	From data compiled by Senopsys, taken from 101 taste assessment studies, it was found that the primary challenge in taste-masking was bitterness at 75%, followed by aromatics (10%), and trigeminal irritancy (8%). In APIs that were fundamentally tasteless, challenges were driven by excipient attributes (3).  

	“The reason these data are critically important is that the formulation strategies for mitigating bitterness, malodor, irritation, and texture are fundamentally different,” explains Tisi. “As these approaches differ, it’s important to correctly identify the aversive attributes at the outset.”

	Predicting whether new compounds will be bitter or not is one of the biggest challenges, according to Karry. “Albeit unknown to most, there is not a clear understanding as to which chemical bonds, functional groups and compounds activate the bitter receptors in the tongue,” she says. “BitterDB, a database with more than 1000 bitter compounds, is available to formulators (4). Machine learning algorithms trained with these molecules are now used to predict bitterness of new compounds. This tool enables formulators to proactively think about methods to suppress bitterness and include in excipients meant for taste masking.”

	Karry continues by specifying that in her opinion the second and most important challenge in bitter formulations is to prevent drug release in the mouth. “Human saliva has a pH range between 6.2 and 7.6,” she states. “The most effective taste-masking approaches employ insoluble polymers that create a barrier that limits water penetration, drug solubilization, and consequently drug diffusion to the surface such that the bitter tongue receptors are not activated, and an aversion reaction is prevented.”

	However, limiting drug release in the mouth brings about other challenges. The most effective taste-masking polymers are insoluble at pH > 5 but will immediately dissolve in stomach acids, explains Karry. “A consideration with using such excipients is that the formulation should allow for complete polymer solubilization in the stomach even with shorter gastric residence times (1 hr) or when the patient is in a fed state (pH 4.2–5.8),” she says. “Special attention should be given to tablets based on multiple-unit pellet systems (MUPS), which show faster gastric emptying times due to their small size and larger surface area. For these, the pellet diameter and coating weight gain need to be optimized with respect to polymer solubilization and drug release rate.”

	Understanding the magnitude of taste-masking challenges is of great importance to Tisi who specifies that although in some instances it may be possible to overcome taste issues with a traditional excipient approach (such as sweeteners, buffers, or flavors) for other ingredients it may be necessary to “sequester” them from the taste receptors to achieve palatability. “Information about the magnitude of the challenge at hand will allow the formulator to prioritize or eliminate certain dosage forms (e.g., the most difficult taste-masking challenges may not be suitable for a ready-to-use oral solution),” he stresses.

	Specific patient populations, such as pediatrics and geriatrics, require more complicated taste-masking approaches. “For these patients, palatable oral formulations are required for acceptable dosing compliance,” comments Tisi. “In recognition, regulations in the United States and European Union are stimulating research into the development of drug products specifically labeled for pediatric dosing.”

	Regulatory requirements and guidance are present in both the US and EU to help companies develop age-appropriate dosage forms for patients. Examples include the Pediatric Research Equity Act (PREA) in the US (5), and the Paediatric Regulation from EMA (6). These requirements typically lead to alternative dosage forms due to difficulties that are encountered by young children in swallowing traditional solid oral dosage forms, confirms Tisi. 

	“However,” he continues, “children are not the only ones who suffer from difficulty of swallowing, a condition known as dysphagia. In the US, dysphagia affects 1 in 25 adults annually, not including patients with certain neurological and degenerative disorders (7). Accordingly, swallowability and palatability are important determinants of dosing compliance for all ages and conditions.”

	Dose and tablet size are important considerations in addition to palatability when designing products for both pediatric and geriatric patient groups, adds Karry. “Parents prefer smaller tablets for their children but minitablets may be difficult to handle by geriatric patients,” she says. “To satisfy both requirements a formulator may opt to create a small tablet with a rocking design. In terms of palatability, children prefer flavored medications, but the opposite is true for older patients. In this case taste-masking polymers can be used to suppress bitterness and achieve a tasteless drug product that also limits drug abuse by children who ‘want more candy’.”

	In addition to the traditional methods of sweeteners, flavors, buffers, and viscosity and pH modifying agents that help avoid dissolution in the mouth, there are other taste-masking technologies that formulators can utilize. “Other technologies, such as salt formation, prodrugs, complexation, and so on, exist,” explains Karry. “Additionally, coating is gaining further traction in the industry as an effective technology for aggressively bitter APIs.” Limitations of coating techniques include imperfections and adequate 

	“Broadly speaking, there are five general masking approaches that are available to the formulator,” states Tisi. “But, each of these approaches comes with its own set of advantages and disadvantages.” (See 

	In terms of future approaches, Tisi believes that there is a trend towards increased mutliparticulate dosage forms. “These serve as an alternative to more established formulation options, but generally require extemporaneous preparation in a dosing vehicle-a complexity for some caregiver situations.”

	Karry agrees that technologies such as microencapsulation, the addition of pH-modifying agents, suspensions, complex formations, solid dispersions, use of taste suppressants and potentiators, and dry coating bitter APIs are being studied; however, she emphasizes that growth of these technologies is relatively marginal compared with film-coating technologies.

	“There is continuing interest in the development of a ‘universal’ taste-masking technology that produces small, spherical particles with a polymeric coating optimized for both taste and bioavailability,” notes Tisi. “Advances have been made in these dimensions as well as taste masking; however, bioavailability and manufacturability of a uniform particle size reportedly remains a challenge.”

	Basic research into how patients perceive taste is continually advancing with many receptors for sweet and bitter tastes being identified, he adds. “This is enabling screening and identification of compounds that can modulate these tastes,” Tisi explains. “However, for drug products, the regulatory landscape is uncertain for these new compounds.”

	Particularly exciting advances for Tisi are those in the field of signal interruption. “A number of players are now working in this field, and each has a proprietary method for discovering novel taste receptor modulators,” he says. “High throughput screening of candidate compounds is a must, as humans possess more than two dozen known bitter taste receptor cells, and a signal interruption chemical must act on the same set of receptors that the drug does.”

	“Now more than ever patients are looking for convenience (i.e., small tablets that can be taken ‘on-the-go’ with minimal or no liquid),” concludes Karry. “As a result, patient convenience and compliance have become important pillars in formulation optimization for new drug products.”

	1. A. Dagan-Wiener, et al., “Bitter or Not? BitterPredict, a Tool for Predicting Taste from Chemical Structure,” 

, Sept. 21, 2017. 
	2. M. O’Mahony, et al., 

, 4 (4) 77–94 (1979).
	3. Senopsys, “Taste Masking-There’s More Beneath the Hood than Bitterness,” 

, 40 D413–419 (2012).
	5. FDA, “Pediatric Research Equity Act | PREA,” 

 [accessed Oct. 16, 2019]. 
	6. EMA, “Paediatric Regulation,” 

[accessed Oct. 16, 2019].
	7. N. Bhattacharyya, 


	Vol. 43, No. 11
	November 2019
	Pages: 26–29

	When referring to this article, please cite it as F. Thomas, “Avoiding Bitter Taste,” 

Palatability is crucial for adherence and compliance to oral drug regimens.


Avoiding Bitter Taste

	As the numbers of biologics in development continue to rise, it is becoming ever more pressing to fully comprehend the potential issues with primary packaging, the optimal route of development, and how to create a patient-centric solution to ensure market success. To understand more about how drug development approaches, primary packaging choices, and regulations impact injectable biologics developers, 

spoke with Janina Lehmann, senior director, Technical Customer Support, North America & Europe at West Pharmaceutical Services.

What are the major formulation and development considerations for biologics?

In drug development, the molecule defines the dosage form. The number of biological therapies in development has continuously risen throughout the past few years, and as a result the subsequent complexity from longer-acting formulations, larger injection volumes, and longer injection durations has also increased. The quality and efficacy of a protein-based drug product formulation strongly depends on the compatibility with the primary container. Therefore, a good understanding of the physicochemical properties of the primary packaging material and validation of its suitability for use is necessary. 

	Generally speaking, maintaining drug product quality, efficacy, and safety over shelf-life is pivotal when approaching biologics formulation. Protein-based drug product formulations in particular pose new challenges to primary packaging. Therefore, developing an effective protein-based drug product formulation requires comprehensive compatibility testing of the primary packaging. This includes testing of extractables and leachables, as well as elemental impurities. 

	Large biomolecules tend to form aggregates under certain storage and transportation conditions; analyzing the interaction of the drug product and container surface under these conditions is recommended. Foreign particulates present in the drug product (e.g., silicone oil) can also cause protein aggregation or adsorption. Using qualified packaging materials that meet compendial standards minimizes the quality risk. 

	Additionally, the viscosity and injection volume of protein-based drug formulations have an impact on the design of an injection device. There are various self-injectors and wearable injectors available that increase patient and healthcare professional convenience in the administration of high-volume and viscous injectable drug products.

How important is a patient-centric approach to developing injectables, and are there any noticeable trends occurring in the industry?

Understanding patient needs is essential to the pharmaceutical quality-by-design (QbD) concept. QbD is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and control based on sound science and quality risk management. To ensure that quality and design of a combination product meet patient needs, critical quality attributes (CQAs) and essential performance requirements (EPRs) must be defined. 

	The increasing trend of patient self-medication, and the increasing number of biological therapies (including gene and cell therapies), are driving innovation in containment and delivery systems for injectable drug products. Self-injectors and wearable injectors increase patient convenience and patient adherence. Increasing the availability of smart, connected devices, likewise improves healthcare decision-making and better patient outcome.  

Could you highlight some of the most important regulatory considerations that impact the injectable drug dosage form decision during formulation and development?
	

Injectable drug products, like any pharmaceutical dosage form, must meet the pharmaceutical quality standards as described in pharmacopeias, and be safe for the intended purpose of use. Likewise, they are required to be free from viable microorganisms, pyrogenic substances, and visible particulates over the product shelf-life. 

	A main challenge for injectable drug products is to achieve good compatibility with the primary container. High-quality container closure systems that meet regulatory requirements reduce the risk of leachables and adsorption and provide container closure integrity. 

	New regulations, such as the 2020 Annex I, EU MDR in Europe, are increasingly focusing on quality risk management in developing and manufacturing sterile drug products and injectable devices. Selecting high-quality drug packaging will reduce quality risks and minimize total cost of ownership.

How can companies benefit from employing an outsourced partner for formulation and development of injectable drug dosage forms? 

For development of injectable drug dosage forms, pharmaceutical companies will benefit from employing an outsourced partner that understands primary packaging and devices, analytical and regulatory requirements, and the drug development process. If a drug manufacturer collaborates with a packaging supplier early on in the development process that can prove beneficial. The packaging technology partner can reduce the development risks by demonstrating the packaging system suitability for its intended use early in drug development. Later in drug development, the packaging partner can help to generate compatibility and performance verification data to support the drug manufacturer’s regulatory submission. 

	Partners should provide integrated solutions for pre-screen, compatibility, and clinical phases I, II, and III. Essentially, partnering should simplify the pharmaceutical company’s journey from molecule to market by reducing development and supply risk, minimizing total cost of ownership, accelerating path to market, and improving the patient experience. 

Experts from West Pharmaceutical Services will be available to discuss this topic and more during CPhI Worldwide in Frankfurt, Germany from Nov. 5–7, 2019-Hall 11.1 Stand 111F62. 

A complete understanding of primary packaging physicochemical properties is necessary in the formulation and development of biologics.

Formulation and Development Considerations for Biologics

	As the United Kingdom fast approaches the deadline for its departure from Europe Union (for the second time), it is possible that Brexit may be delayed even further. The UK government remains at loggerheads, with furore over the recent prorogation, a court ruling stating that the suspension was unlawful, no clear indication a plausible deal will be achievable, and a bill prohibiting a ‘no-deal’ scenario. Another Brexit extension is becoming a possibility.

	However, even if the UK government requests another extension, there is no guarantee that the other countries of the European Union would agree. So, where does this uncertain situation leave the pharma industry both within the UK and across Europe?

	There have already been significant changes as a result of Brexit that have impacted the pharma industry. The relocation of the European Medicines Agency (EMA) from London to Amsterdam was completed in March 2019 and resulted in the agency restricting activities and focusing on core tasks while adjusting to the move and subsequent loss of staff. 

	Companies have been stockpiling and working on contingency planning to help ensure the supply of medicines post-Brexit is minimally affected. Some pharma companies have stopped investments into the UK altogether, waiting until Brexit is finalized or there is at least some clarity on the situation, and others have opened facilities in countries that will remain in the EU to avoid business disruptions.

	Parliamentary bodies and industry associations both in the UK and EU have been releasing guidance information to help pharma companies prepare for Brexit. These types of documents have been particularly prominent for the potential of a ‘no-deal’ scenario, which is considered to be the ‘worst-case’ scenario for the pharma industry.

	In August 2019, the UK government’s official report (Operation Yellowhammer) on the probable outcomes of a ‘no-deal’ Brexit was leaked (1), which highlighted potential disruption to medicines supply that could last up to six months. The Channel port disruptions are underlined as a particular issue of the supply of medicines and medical products, which is an issue that cannot always be overcome by stockpiling as a result of limited shelf-life (2).

	Although the government has pledged funding to help with medicines supply in the event of a ‘no-deal’ scenario, a recent report from the National Audit Office stressed that there is a significant amount left to do so that a steady flow of medicines is assured (3).

Continuous ‘no-deal’ preparations challenging

	The full extent to which the pharma industry will be affected by Brexit is yet to be determined and will very much be influenced by any potential deal that may (or may not) be agreed upon by officials in both the UK and EU. And as UK Prime Minister, Boris Johnson, has firmly stated that his political policy will see the UK leaving Europe on 31 October 2019 with or without a deal, regardless of the Benn Act (a recently passed law that prohibits ‘no-deal’), the waters surrounding Brexit seem to be muddier than ever before.

	For the pharma industry, however, continuous preparations for a ‘no-deal’ Brexit is a challenging prospect, as stated by the Chief Executive of the Association of the British Pharmaceutical Industry, Mike Thompson, earlier this year (4). “Leaving the EU with a deal in place remains the best way to minimize any potential disruption to medicines supplies,” Thompson said.

	1. The Guardian, “No-Deal Brexit: Key Points of Operation Yellowhammer Report,” 

, 18 August 2019.
	2. BBC, “Brexit: What does Yellowhammer Say About No-Deal Impact?” 

, 20 September 2019.
	3. NAO, “Exiting the EU: Supplying the Health and Social Care Sectors,” 27 September 2019.
	4. ABPI, “ABPI Response to Government ‘No Deal’ Guidance,” 

	When referring to this article, please cite it as F. Thomas, “The Never-Ending Brexit?” 

With no plausibly approvable deal on the table in the UK government at the moment, it is possible that Brexit could be extended even further.


The Never-Ending Brexit?

Because oral solid dosage forms are still the most common way in which drugs are administered, dissolution of the dosage form after it is swallowed, namely the rate at which the active ingredient is released into the body, is a critical facet of drug development. “Dissolution testing is an essential analytical procedure that’s required as part of the final release investigation for solid oral dosage forms to control product quality, stability, and batch-to-batch consistency,” confirms Meike Eckert, head of Dissolution Laboratories, Evonik Health Care. “As the rate of dissolution can significantly affect bioavailability, the goal of dissolution tests and associated acceptance criteria should be to identify batches with unacceptable bioavailability.”

	The primary functions of a dissolution test during early stages of development are to characterize therapeutic efficacy, bioequivalence, and bioavailability of API. During later stages of the development process, dissolution testing is also used for quality control (QC) purposes. “The type of dissolution testing performed along with the information required from the testing will change as the molecule progresses from the early stages of development to later in clinical development and towards product registration,” says Charlotte Clay, head of Analytical Development, Pharmaceutical Analysis, Quotient Sciences.

	“At the initial stages of characterizing and selecting the API, 

dissolution testing can be performed to aid determination of the Developability Classification System (DCS) classification of an API, and in turn provide useful guidance on the best formulation development strategy for a molecule,” Clay continues. “In later stages of development, dissolution testing is used as a QC procedure to detect the influence of critical manufacturing variables on a drug product.”

	During early drug development stages, it is possible to use a biorelevant dissolution method to determine how a formulation may react in media, such as fasted simulated gastric fluid (FaSSGF) and fasted simulated intestinal fluid (FaSSIF), that closely mimics conditions found inside the human body, Clay explains. “This methodology provides a prediction of how a formulation will behave within the body and ensure that the most appropriate formulations are taken forward into clinical trials,” she says.

	After the optimal formulation has been chosen to progress, dissolution methods specifically aimed at assessing quality and stability are developed. “These methods may not be biorelevant (standard acidic and phosphate buffered medias are typically used), but they are able to distinguish batch-to-batch variability as well as any changes in the formulations’ dissolution performance that could affect product stability,” Clay confirms.

	Once pharmacokinetic (PK) data have started to be collected from clinical trials of the chosen formulation, it is appropriate to develop a biopredictive dissolution method. When used in combination with PK data, it is possible for developers to set up 

 correlations (IVIVC), which can be used to optimize formulations and determine equivalence for generic or modified versions of originator drug products, states Eckert.

	“By following a quality-by-design (QbD) approach, risk assessments and definitions for quality target product profiles can be used throughout the clinical development and commercial lifecycle to identify potentially high-risk formulation and process variables,” summarizes Eckert. “Dissolution testing can also achieve an improved product and process understanding to develop an appropriate control strategy.” 

	Of paramount importance for dissolution testing is the assurance that the conditions used for testing are appropriate and correct for the product that is being tested, as well as for the information that is hoped to be gained from the test, stresses Clay. “There are many variables when it comes to dissolution testing from the type of apparatus and the dissolution media used, through to the small but important decisions on parameters, such as paddle/basket rotation speed, the use of sinkers, and the number of sampling time points, to name but a few,” she explains. “Small changes to these variables can have a big impact on the data generated; for example, the sinker mesh size used can have a direct impact on the release rate of the formulation, so it is therefore important to control these parameters and specify them in the analytical test method.”

	Additionally, Clay emphasizes that as a result of an increasing number of poorly soluble molecules entering the development pipeline, the number of ingredients falling into a DCS class II or IV are also rising. “As such, choosing the correct dissolution media where sink conditions can be achieved is becoming more of a challenge when developing dissolution methods,” she says.

	In agreement, Eckert highlights that it can often be necessary to add solubilizers, such as sodium lauryl sulfate, at an appropriate concentration to achieve meaningful dissolution results when dealing with poorly soluble ingredients. “During the formulation development process, it can be challenging to identify the right dissolution test methods to predict how the target formulation will perform 

to reduce risk during future clinical studies,” she continues. “Based upon the physicochemical characteristics of the API and the type of formulation, the use of media with different rates of complexity can be employed. These media options can range from plain buffers up to biorelevant media and the potential addition of digestion enzymes.”

Defined dissolution apparatus and development of new tools

	Currently, there are seven different types of dissolution apparatus defined in the 

-basket type, paddle type, reciprocating cylinder, flow through cell, paddle over disc, rotating cylinder, and reciprocating disc. Of the seven apparatus, basket type (apparatus I) and paddle type (apparatus II) are most commonly used for oral solid dosage forms but many different product types, from capsules to creams, can be testing using the apparatus defined in the 

Apparatus I and II are the most commonly used dissolution apparatus for solid oral dosage forms and are versatile in enabling the development of many types of dissolution methods, from those for formulation development purposes to those used for QC testing of commercial batches,” confirms Clay. “There are also a number of more bespoke dissolution apparatus/techniques being developed and used as drug products become more complex and the search for a more biopredictive technique continues.” 

	In concurrence, Eckert notes that development of newer 

tools has occurred as a result of the rising number of APIs with more complex physicochemical characteristics and the more stringent regulatory requirements being demanded for the prediction of 

 behavior. “In addition to Apparatus III and IV (reciprocating cylinder and flow through cell), which are candidates for the prediction of detailed gastrointestinal transit with multiple test media or bioequivalent volumes, there is a growing toolbox of other emerging systems that are now offered by university spin-offs, such as Physiolution or other specialized companies for certain specific challenges,” she says. 

	Giving an example, Eckert explains that multiple providers now offer services to combine dissolution testing with simulated mechanical stress. “These combination tests offer additional benefits for dosage forms that are sensitive to mechanical stress, such as delayed release capsules,” she adds. “They can also be useful in the development of generic products to compare eroding and non-eroding matrices.”

	Volumes can be problematic when determining the most appropriate dissolution test to use, stresses Eckert. The commonly used apparatus are limited for use with media volumes of between 500 mL and 1000 mL, which can restrict the physiological relevance. However, using high volumes for dissolution testing can lead to an overestimation of 

 performance. “To better reflect conditions within the human gastrointestinal tract, the use of mini-paddles combined with smaller vessels can sometimes be advantageous,” Eckert says. “However, this method is not yet considered by the pharmacopeias.”

	Clay continues by highlighting the fact that there has been an escalating use of modified and non-compendial apparatus in the field of dissolution testing over recent years. “These apparatuses are being utilized to offer novel perspectives on different dosage types, delivery devices, and formulations, with the goal being to make dissolution results more biorelevant,” she states. “As a result, previous ‘fringe’ techniques such as intrinsic dissolution, small-volume dissolution, and dissolutions using enhancer, immersion, or extraction cells are becoming more widely adopted.” 

	Furthermore, advancements in detection techniques are also enabling testing, either online or in real-time, of more complex, multi-component formulations, Clay confirms. With the added capabilities afforded by these new detection techniques, developers can achieve a comprehensive data set, which provides a better understanding of the interactions of APIs and excipients in product formulations.

	Globally, various pharmacopeias provide clear outlines for apparatus, procedures, and evaluations that will help developers to fulfill the dissolution testing criteria of regulatory bodies. For example, USP has several chapters, including 711, 1092, and 1225, detailing preliminary assessments, method development, analysis, automation, validation, and acceptance criteria (1–3). In 

section 2.9.3 (4), developers can find information on apparatus, procedures, and evaluations for acceptance criteria also. 

	“Since 2014, Europe has also started following the USP approach of publishing individual formulation monographs containing dissolution methods and acceptance criteria,” adds Eckert. “In the US, additional information is also publicly available in the dissolution methods database (5) of FDA.” 

	Further information can also be found on the physical operating conditions of the dissolution testers, confirms Clay, with guidelines covering dissolution testing for immediate release, delayed release, and extended release drug formulation types. “However, given the complexities of the human body, physiology, and chemical/biological interactions that take place, it can be difficult to solely rely on the dissolution test as a way of predicting how a drug formulation may perform 

,” she stresses. “The use of biorelevant media can aid such assessments, but there is no way of understanding how closely the dissolution test may predict 

performance without performing clinical studies.”

	The European Medicines Agency (EMA) also provides guidelines on the investigation of bioequivalence, reveals Eckert. “These guidelines describe the use of dissolution studies to waive a bioequivalence study in applicable cases and the evaluation of similarity of dissolution profiles,” she says. “The use of dissolution data in IVIVC approaches is also explained in EMA’s guideline (6) on the pharmacokinetic and clinical evaluation of modified release dosage forms.” 

	Because dissolution testing is fundamental for the assessment of the performance of oral formulations and is widely used around the world, much work has been done to create a globally uniform approach. The International Council for Harmonization (ICH) has worked with various pharmacopeias to harmonize many of the dissolution testing methodologies (specifically 

I and II Apparatus) so that they are standardized across many different regions, Clay iterates.

	“Dissolution is a harmonized technique across many pharmacopeias in which dimensions of the equipment used and operating parameters are clearly defined and documented,” Clay continues. “Thanks to this harmonization, successful transfer of validated dissolution methods from one laboratory to another is made to be relatively straightforward.”

<711>, “Dissolution” (US Pharmacopeial Convention, Rockville, MD, 2011).
	2. USP, 

<1092>, “The Dissolution Procedure: Development and Validation” (US Pharmacopeial Convention, Rockville, MD, 2012).
	3. USP, 

<1225>, “Validation of Compendial Procedures” (US Pharmacopeial Convention, Rockville, MD, 2012).
	4. European Pharmacopoeia, 

. “Dissolution Test for Solid Dosage Forms” (European Medicines Agency, London, UK, 2008).
	5. FDA, “

,” [accessed Sep. 18, 2019].
	6. EMA, 

Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms 


	Vol. 43, No. 10
	October 2019
	Pages: 44–47

	When referring to this article, please cite it as F. Thomas, “The Fundamentals of Dissolution Testing,” 

In this article, experts discuss the fundamentals of dissolution testing and highlight the challenges that are surfacing as a result of the increasing numbers of poorly soluble molecules entering the development pipeline.


The Fundamentals of Dissolution Testing

Lipid-based approaches to drug delivery have been extensively researched and have gained importance within the bio/pharma industry for their ability to enhance bioavailability of drug products. This capability to enhance bioavailability is becoming ever more desired in recent times due to the fact that increasing numbers of molecules entering the drug development pipeline are poorly soluble.

	“As of late, more than 70% of new chemical entity (NCE) molecules are poorly soluble, with moderate lipophilicity (LogP >2),” says Ravinder Kodipyaka, head, formulation R&D, Custom Pharma Services, Dr Reddy’s. “As a result, industry is witnessing opportunities in novel drug discovery for the formulation of new NCEs in lipid-based drug delivery systems (LBDDS) so that bioavailability is improved.”

	“Lipid-based formulations offer a tremendous solution for molecules exhibiting poor solubility and bioavailability,” Kodipyaka continues. “These formulations provide excellent solubilization capacity; improve permeation; overcome transporter, enzyme-based inhibitions; and support lymphatic transport, thereby overcoming major roadblocks for achieving optimum bioavailability.”

	Using lipids to enhance oral bioavailability is a popular choice, adds Michiel Van Speybroeck, head of formulation, Ardena. “When an API is dissolved in a lipid formulation and subsequently administered, the API is presented to the gastrointestinal (GI) fluids in a predissolved form, which avoids slow dissolution from the crystalline form,” he notes. “The great advantage that lipids and lipophilic excipients offer over water-miscible solvents is that they are less likely to lose solvent capacity on dilution with the GI fluids. On contact with water, lipophilic excipients phase-separate and form a coarse or finely dispersed emulsion in which the API is sequestered. This protects the API from precipitation in the aqueous phase.”

	Furthermore, Vincent Plassat, lead product development scientist, Catalent, emphasizes that by delivering drugs in a solubilized form, dose-uniformity can be improved, minimizing patient-to-patient variability. “There is a lot of precedent for the use of lipid-based drug delivery systems as a result of their value to drug developers and ultimately to patients. LBDDS are extremely versatile because there are many excipients and combinations of excipients that can be used in their development,” he explains.

	Along with improved dose uniformity, LBDDS are also capable of mitigating food effects (1), Plassat confirms. “For very lipophilic drugs with a LogP value greater than five, formulation of long chain fatty acids can improve lymphatic uptake and bypass the liver. In addition, lipid-based formulations can maintain their solubility throughout the entire journey of the API through the GI tract, allowing higher absorption,” he says. “This is unlike non-lipid-based formulations, which exhibit supersaturation, decreased solubility, and lower absorption.”

	Administration of lipid-based formulations is possible across several routes-oral, injectable, and topical-and depending on the lipophilic nature of a drug, it is possible to determine the optimal lipid delivery system using the Lipid-Formulation Classification System (2), explains Kodipyaka. Employing a suitable lipid excipient component can also aid in modulation of drug release. “The greater the hydrophobicity of the lipid excipient the slower the drug release due to reduced water penetration,” he adds.

	Being able to control drug release is important so that rapid, high drug plasma level peaks are avoided, which can cause unwanted side effects in patients, notes Ellie Au, product development scientist, Catalent. “A slower release may also protect the drug from degradation in the stomach and facilitate release of the drug throughout the GI tract to improve absorption. Self-emulsifying lipid formulations typically have faster drug release than those lipid formulations that require digestion. The use of waxes, which are solid at room temperature, creates a matrix for modified release. The drug is therefore released with a controlled kinetic as the matrix slowly erodes,” she says.

	“Drug release can be further modulated by incorporating pore formers, hydrophilic polymers, and surfactants in the composition or by virtue of a process that creates a more porous structure,” Kodipyaka comments. “Drug release is the important determinant to ensure maximum bioavailability at the site of action. Thus, lipid formulations could be tailored to achieve desired drug-release kinetics by careful selection of lipid excipients.”

	Lipid-based formulations offer versatility and compatibility in terms of generally recognized safety, route of administration, and capability to overcome bioavailability issues. However, with this versatility, some challenges with LBDDS arise, such as stability issues and drug loading, reveals Karunakar Sukuru, vice-president, Product Development (US & EU) Softgel & Oral Technologies, Catalent. 

	Drug loading, for example, can be quite low in LBDDS as a result of the improved solubility offered. “Nevertheless, drug loading is a challenge faced by many other bioavailability enhancing technologies,” Sukuru adds.

	For Kodipyaka, a common challenge associated with lipid-formulations is ingredient stability issues, particularly when using liquid formulations rather than solid forms, and drug precipitation during storage or contact with 

GI fluids. “After administration, dilution and digestion effects will lead to a reduction in the solvent capacity of the lipid formulation. As a result, the API that was initially in solution may precipitate, and this may reduce the bioavailability-enhancing potential of the formulation,” agrees Speybroeck. “While lipid formulations are generally less susceptible to these effects than those based on water-miscible solvents, some precipitation may still occur. The magnitude of this effect can be assessed using 

techniques that consider the effect of formulation digestion.”

	Therefore, appropriate design of LBDDS is necessary to ensure that drug precipitation upon exposure to GI fluids is indeed avoided, Sukuru confirms. “Understanding the mechanism and predicting 

performance of LBDDS has gained a lot of attention recently,” he says. “Many lipid excipients are naturally derived and contain multiple lipids (e.g., mixtures of mono-, di-, and triglycerides). There may be issues as ratios of lipid components change from batch-to-batch. Because of these variables, it is recommended that drug developers work with experts who have extensive experience and knowledge of the development of LBDDS.”

	Another challenge experienced with lipid-based formulations is that of Ostwald ripening, which is where small particles dissolve and then re-deposit onto larger particles due to surface energy instability. “Ostwald ripening is a major challenge for lipid-based formulations, particularly for injectable products,” says Kodipyaka. “There are a limited number of approved, safe emulsifiers commercially available that can stabilize the emulsion system; hence, it would be very challenging to develop emulsion systems with the desired target product profile.”

	“Finally, while the excipients used to construct lipid formulations are usually quite inert, many of these contain impurities, such as peroxides, aldehydes, or formic acid, that may trigger degradation pathways that are not seen when the same API is formulated in a solid formulation,” specifies Speybroeck.

Available techniques and their limitations

	Assessing the precipitation risk of lipid-based formulations as a result of dilution and digestion is possible using 

experiments. These tests are more complex than standard dissolution tests but are capable of providing a more reliable indicator of lipid formulation performance, notes Speybroeck.

lipolysis experiments have been the traditional experiment to study a LBDDS mechanism and correlate it with 

performance,” confirms Au. “Newer approaches, such as kinetic solubility measurements, are gaining interest to correlate with 

	Sukuru adds that a main limitation of current techniques that are aimed at overcoming challenges associated with lipid-based formulations is that all the work is undertaken in a closed system, whereas the human body is dynamic and always in motion. “A variety of new techniques and tools are available to quickly evaluate lipid-based formulations. One such tool is fiber optic dissolution testing, which allows for monitoring of dissolution profiles in real-time in a variety of biorelevant media and makes it easier to compare the performance of the formulation without the need for complex and lengthy analytical methods. It is also easier to asses any impact of the media modification,” he says. “With such advances in analytical instrumentation, product development can be expedited and made more robust through the generation of data and providing the opportunity to challenge different parameters of the formulation earlier in development.”

	There is also the emergence of technologies in the field to enhance API loading of lipid-based formulations, adds Speybroeck. “Some researchers have reported on the use of supersaturated lipid formulations (3), whereby the API loading is increased by subjecting the lipid formulation to a heat-cool cycle,” he states. “This way, the concentration of API in the formulation is increased beyond its equilibrium solubility, which may lead to several-fold increases in API loading. This technique may be a viable option to reduce administration volume in preclinical and early clinical development. However, the utility for commercial products is more limited given the risk of API precipitation during storage, as the API is present at concentrations above its equilibrium solubility in the formulation.”

	Regarding ingredients, Speybroeck notes that lipophilic salts are developing within the industry. “While traditional pharmaceutical salt forms are usually developed using small, hydrophilic counterions in an attempt to increase aqueous solubility, lipophilic salts are constructed with large, lipophilic counterions,” he says. “These salts may exhibit greatly depressed melting temperatures relative to the free form of the API and therefore also exhibit much higher solubility in lipophilic vehicles.”

	In terms of unsaturated lipid components, which are prone to lipid peroxidation, formulators can employ saturated medium chain triglycerides along with appropriate antioxidants, explains Kodipyaka. “Excipient compatibility and stress stability studies during early stage development help formulators choose the right excipients according to the degradation pathway of the drug,” he says. “Decreased mobility by making semi-solid formulations also can help to physically and chemically stabilize the formulation.”

	Additionally, alternative ingredients for capsules are coming to the fore, such as the use of hydroxypropyl methylcellulose (HPMC) or polyvinyl alcohol, instead of traditional gelatin-based capsules. “These ingredients are chemically and thermally stable and are less prone to humidity compared to gelatin-based capsules,” Kodipyaka confirms. “Furthermore, with the invention of liquid encapsulated micro-spray sealing technology, problems that were common with the conventional banding approach have been resolved.”

	As molecules entering the drug development pipeline are increasing in size and becoming more lipophilic and chemically diverse, solubility challenges are also rising and can lead to a higher level of drug susceptibility to food effects, notes Au. “The broad range of lipid excipients available offer many options to customize formulations to meet the specific needs of the molecule,” she says. “Investing time and effort early in the development of a LBDDS can result in significant savings in time and overall development costs, and often with a better outcome.”

	With an expanding proportion of drugs gaining fast-track designation, particularly for those therapies aimed at unmet medical needs, the benefits of LBDDS, which were primarily used to introduce life-saving drugs such as HIV proteases and anti-cancer treatments, are apparent, notes Plassat. “For example, within the industry, there has been a growing interest in peptides and other macromolecules due to their high specificity and potency,” he states. “The molecules are usually more sensitive to degradation, and lipid-based formulations can provide them with a better environment for long-term stability, and/or protect them from degradation in the GI tract.”

	Yet, developing a lipid-based formulation essentially remains an empirical endeavor, notes Speybroeck. “Given the plethora of lipids and lipophilic excipients available, initiating a lipid formulation development may seem like a daunting task,” he adds. “However, great progress is being made in in-silico (computer-assisted) prediction of solubility. Adoption of such techniques may dramatically reduce the initial development effort.”

	Thanks to these formulation design advancements in addition to new technologies that can enhance API loading and an improved understanding of how lipid-based formulations perform 

, Speybroeck anticipates an enhanced adoption of the lipid approach in the future. “I believe we will witness a steady increase in the use of lipid formulations in clinical and commercial drug products going forward,” he says.

	Taking a lipid-based approach for the formulation and delivery of new molecules with large molecular weights and high lipophilicity has shown great promise, stresses Kodipyaka. “However, technology development and implementation in the area of lipid drug delivery needs to be expedited to catch up with the discovery pace,” he summarizes. “A multi-disciplinary approach is required to overcome limitations pertaining to development of lipid formulations for poorly soluble molecules. Knowledge of lipid chemistry, predictive in-silico models, nanotechnology, and bio-pharmaceutics coupled with advanced characterization techniques would be helpful in resolving complex issues moving forward.”

, 43 (11) 1743–1758 (2017).
	2. V. Jannin, et al., 

, 80 (6) 1011–1020 (2018).
	3. J. Brouwers, M.E. Brewster, and P. Augustijns, 


	Vol. 43, No. 10
	October 2019
	Pages: 28–32

	When referring to this article, please cite it as F. Thomas, “Overcoming Bioavailability ‘Roadblocks’ with LBDDS,” 

Lipid-based formulations provide a versatile solution to bioavailability issues, but a multi-disciplinary approach is needed to overcome limitations with poorly soluble compounds.
