Image showing scientist performing experiment

INTRODUCTION

The development of orally administered small molecules  is becoming more challenging as an increasing number  of molecules in pipelines have poor aqueous solubility  and bioavailability. This article will introduce an efficient  development process that can help deliver the right  clinical candidate, optimal formulation strategy and the  most appropriate dosage form to clinic. It will also review  some established data-driven approaches to formulation  development, focus on the value proposition for discovery  biopharmaceutics and discuss a preformulation toolkit for  drug discovery.

VALUE PROPOSITION FOR DISCOVERY BIOPHARMACEUTICS

Drug discovery and development is a lengthy and costly  undertaking, but well-planned early stage work can help  de-risk development, reduce attrition, avoid excessive late  phase efforts and decrease delays in patient access. The  drug discovery process begins with the validation of drug  targets and pathways, then moves into assessment of

pharmacokinetic-pharmacodynamic responses and/or efficacy  in preclinical models, establishment of structure activity  relationships (SAR), and identification and optimization of lead  compounds.

Discovery biopharmaceutics plays different roles at each stage  of discovery and development. In the early phases of discovery,  biopharmaceutics groups often support compound screening  with formulation development for low-dose pharmacokinetic  (PK) studies and provide physical chemical assessments with  the goal of achieving exposure in preclinical experimental  models. In the optimization phase, the biopharmaceutics  group provides a full developability assessment and physical  form recommendations to ensure consistent exposure is  achieved across subsequent studies. 

Image showing case study of Bioavaibility

As the program moves  forward to toxicology studies, it is essential to develop  formulations that can achieve sufficient exposure at high doses to establish the therapeutic index for  the development candidate compounds. At  each stage of development, different aspects  of exposure are addressed, and it is important  to understand the factors that can affect exposure.

As an orally dosed compound transits through  the gastrointestinal (GI) tract, absorption, gut metabolism and liver metabolism will all  influence how much of the compound reaches  the bloodstream. The fraction of the oral dose  that is absorbed and avoids gut and liver  metabolism to reach the systemic circulation is  the bioavailable fraction. Formulators can only  impact the fraction of the dose absorbed, thus  it is important to understand the processes  that affect the bioavailability of a compound  and where formulation optimization can  resolve the issue, or where a new candidate  compound needs to be selected.

The case study illustrated in FIGURE 1 shows  two compounds, each with a bioavailability  of 24%. Compound 1 is 30% absorbed with  80% of the absorbed dose escaping gut  and liver metabolism. Compound 2 is 80%  absorbed with 30% of the absorbed dose  escaping gut and liver metabolism. Since  only 30% of compound 1 is absorbed and a  large portion of the absorbed dose escapes  metabolism, it is possible to improve its bioavailability by investigating the root cause of the low fraction absorbed and selecting a  formulation approach that overcomes that  issue. Compound 2, on the other hand, already  has an 80% fraction absorbed; therefore,  further improvements in fraction absorbed are  unlikely to significantly improve bioavailability,  and as most of the absorbed fraction is  metabolized, it is advisable to select a different candidate.

PREFORMULATION TOOLKIT FOR BIOPHARMACEUTICAL RISK ASSESSMENT IN DRUG DISCOVERY

Several simple tools can be used for  biopharmaceutical risk assessment early in  discovery, which include the developability  classification system (DCS) and preclinical  dose number (PDo) evaluation. These tools  categorize new chemical entities by the key  factors that limit oral absorption and have  the advantage of requiring minimal data  such as in vitro permeability, solubility, and  the dose. The solvent-shift solubility assay  assesses whether a compound can maintain supersaturation in intestinal fluids even if it has  poor thermodynamic solubility. Additionally,  absorption modeling (e.g., using GastroPlus®)  can help predict whether the compound can  achieve the desired exposure in toxicology  studies and identify the critical factors and  parameters for oral absorption.

  • Compounds that fall in DCS class I should achieve sufficient exposure using conventional formulations without  solubility or permeability limitations. DCS  IIa compounds can achieve sufficient  exposure with simple strategies that  improve the dissolution rate.
  • DCS class III compounds are permeability limited in their absorption and formulation is unlikely to affect exposure.
  • DCS class IIb compounds are solubility limited with high permeability. Exposureof compounds in this class can be  achieved using an enabled formulation.
  • DCS class IV compounds are solubility  limited and have low permeability and  are therefore the highest risk category for  poor oral absorption. These compounds  will likely require an enabling technology.

Many drug candidates are weak bases that  have good solubility in the low pH of the  stomach but have poor solubility at the higher  pH conditions of the intestine where most  commonly drug absorption occurs. At the  higher pH, they can precipitate, leading to  poor absorption and inconsistent exposure.

The solvent-shift solubility assay helps  prioritize compounds that maintain high  supersaturation when switching from the low  pH in the stomach to higher pH conditions in  the intestines. Compounds that can maintain  supersaturation are more likely to have good  exposure when dosing in vivo.

Absorption modeling helps formulators  understand what parameters are limiting  exposure and evaluate the risk of seeing non-  proportional dose exposure in PK studies.

In the preclinical stage, it can help validate  early in vivo PK models, determine absorption  limitation, and aid in toxicology study and  formulation selection.

Based on the early PK data and physiochemical  characteristics of a given compound,  GastroPlus software can be used to perform  multi-parameter sensitivity analysis. The  software can help scientists understand the  effects of solubility, permeability, particle  size, or dose on the fraction absorbed. For  example, in the development of a suspension  formulation for animal studies, it is critical to select an appropriate particle size to  ensure optimal exposure of the compound.  PBPK modeling, with the inputs of available  data, can be used to predict the effect of  increasing dose and varying particle size on the expected fraction absorbed and help  select a suitable particle size range for the  compound in the formulation.

PBPK modeling can also help rank  developmental compounds according to  the risk of poor exposure from conventional  formulations. A low risk compound has  good predicted exposure across the  toxicology and anticipated human dose  range when delivered using a conventional  formulation. Medium risk compounds may  have poor exposure from a suspension or conventional tablets, but they can  maintain supersaturation and modeling  shows absorption can be improved.

These compounds have the potential to  achieve target exposures using enabling  technologies and further formulation  development is recommended. High risk  compounds will have either high clearance  or poor solubility and poor supersaturation  potential. They will be very difficult to  develop into a formulation that will improve  exposure. When high risk compounds are  identified, it is recommended to terminate  their development and go back to the  optimization phase to use SAR to improve  upon these intrinsic properties.

A recent case study demonstrates the utility  of PBPK modeling in formulation selection  for dose ranging toxicology studies. The lead  compound showed dose proportional PK in  rats and the team wanted to move forward  at risk to a two week toxicology study in both  rats and dogs. The PBPK model and in vitro  solubility data can predict the impact of the  difference in biology between rats and dogs  on the effective duodenal solubility of the  API. In this case, it was important to consider  the duodenal bile salt concentrations in the  two species, where dogs in the fasted state  have a four-fold lower bile salt concentration  compared to rats. 

Image showing Development of drug process

Due to the difference in  bile salt levels, the effective in vivo solubility in a dog will be about four-fold less than in  a rat. In this scenario, dosing the dogs with  the API formulated as a simple suspension  may lead to solubility limited exposure. Before  moving forward with the toxicology study in dogs, it was recommended to first confirm the  appropriate formulation approach that can  achieve the required exposure.

In the clinical phase, PBPK modeling can  be used to help predict first in human  (FIH) doses, understand dose exposure relationships, formulation bridging, in vitro/in  vivo correlations and predicting absorption in  special populations.

STRATEGIES TO ACCELERATE YOUR MOLECULE’S DEVELOPMENT PATH

With the focus on small molecules for  oral development, strategies capable of accelerating the development path can be  broken into three areas: selecting the right  molecule, right formulation technology, and  the most appropriate dosage form.

Selecting the right molecule

The process  of selecting the right molecule is shown in  FIGURE 2.

The top section in blue illustrates the  development of the API. Achieving optimal  drug targeting and potency in the controlled  laboratory setting of the medicinal chemist  is very different than in a dynamic in vivenvironment of the patient. It is therefore important that the medicinal chemist engages  with the drug product formulator early on.

During the development process,  understanding the bioavailability of a drug  candidate is critical to predict its success  as an oral drug candidate. Bioavailability determination in preclinical studies requires  the administration of the drug via both the intravenous (IV) and oral routes and  then comparing the resultant PK profiles.

The IV route is used as the comparator for  determining oral bioavailability as it inherently  has 100% bioavailability since the drug is  delivered directly into the blood stream. 

Image showing best PK in rodents

When  dosing animals in these early studies, it is  important to collect reliable data, as this data will help build early PBPK models that will  drive future development decisions. Sometimes, mistakes can be made when  formulating for early PK studies and  toxicology studies:

  • Many small molecule drugs in development will fall into the DCS IIb category where their equilibrium solubility severely limits their absorption  potential. A study using an oral  suspension for a DCS IIb molecule will  not provide the exposure required to understand the attributes of the  molecule as a drug. Formulation of the  candidate using enabling technologies  will be needed to improve solubility and  ensure adequate exposure in animals.
  • During early formulation development, it is important to evaluate the API’s solubility and risk of precipitation in  simulated gastric fluid and simulated  intestinal fluid. The drug not only  needs to be in solution, but also stayin solution as it moves throughout the  intestinal tract.
  • It is important to understand the properties of the excipients and vehicles.
  • used to dose the animals. A perceived  easy solution for dosing animals is the  administration of the drug dissolved in  dimethyl sulfoxide (DMSO). DMSO may  be able to solubilize a wide range of  molecules, however, it can alter the drug  absorption process and may skew the  data collected. It is important to keepin mind that not all excipients are truly  inactive in the body.

When preparing injectable formulations, it is  critical to use well tolerated excipients that can  adequately solubilize the API and manage the  risk of precipitation in plasma. Precipitation  risks are critical with injectables, as there can be serious adverse events if the drug  precipitates after injection.

Using optimized preclinical formulations  based on our understanding of the DCS  classification of the drug will ensure reliable  pharmacokinetic data. Subsequent PBPK  modeling of these early studies can be  used to rank developability potential of lead  candidates. An example of five typical drug candidates for lead consideration are shown  in FIGURE 3. All aspects of the drug should be evaluated to select the best candidate to move to next stage of development.

Image describing how to create a solid dispersion

  • Molecule 3 can immediately be eliminated because it has high first-pass loss, which cannot be overcome through  formulation.
  • Molecule 1 is also eliminated. Although improving solubility may result in reasonable bioavailability, a DCS class IV  compound has permeability issues that  are difficult to overcome.
  • Molecule 2 has great potency, and if DCS IIb solubility challenges are overcome, the highest bioavailability is  possible.
  • Molecule 5 could be considered because it is a DCS I and will therefore not need for an enabling formulation, however, it has  high first pass loss.
  • Molecule 4 may be the best of all the candidates. It is a DCS IIa molecule, which can be formulated to improve kinetic  solubility of the drug through a simpler  approach like micronization. This saves  time, money and has lower overall risk.

Selecting the right drug formulation technology

As there are no solubility or permeability  issues with DCS I molecules, the focus is on  a formulation strategy for DCS II molecules.  DCS IIa molecules are dissolution rate  limited. Use of pharmaceutical salts can  help stabilize an API, improve solubility and  may be a good choice for moving a DCS IIa  to a DCS I.

However, if enabling techniques  are still needed, using the salt form can  possibly introduce unwanted interactions with equipment or add unwanted bulk to the  formulation. Depending on the properties of  the salt and the technique needed to improve  bioavailability, formulators may prefer to work  with a free form of the molecule. Additional approaches for DCS IIa molecules include  micronization to increase surface area and  utilizing a hydrophilic co-solvent.

A surfactant or polymer can be added to assist  in wetting and dispersion of the particles. When utilizing micronization, however, the  API must be monitored for possible form  change since energy is being introduced into  the system to break down the particles. Flow  properties may be changed as well.

The hydrophilic co-solvent approach presents  the drug in a liquid form which overcomes  the need for drug particles to dissolve in the intestines. However, this approach does  not contain any components that can help  maintain the drug in solution and is not a  reliable strategy for DCS IIb molecules.

DCS IIb molecules are equilibrium solubility  limited. The two most common DCS IIb  approaches are amorphous systems and lipid  based systems. Although some molecules can  work in either system, the screening process  usually identifies the best option. Amorphous  systems are good for highly crystalline drugs  (“brick dust” molecules). Spray drying and hot  melt extrusion are typically used for producing  a solid dispersion that can be made into tablets  or capsules as the final dosage.

 Lipid based systems are well suited for high log P molecules,  while also providing additional benefits like  protection from oxidation and improved  content uniformity, which is especially helpful  for low dose drugs. Liquid APIs can be easily  incorporated into lipid based systems as well.

To create a solid dispersion using spray drying,  the drug and polymer are dissolved in an  organic solvent to break down the crystalline  lattice of the drug and then the resultant  solution is sprayed into a drying chamber to  form amorphous solid particles as the solvent  evaporates. Mixed with additional excipients,  the powder is usually pressed into a tablet.

A main consideration for spray drying is that  the drug must be soluble in a solvent. Also, at  a commercial scale, large amounts of solvent  would be necessary. With hot melt extrusion,  instead of dissolving in a solvent, the API and  the polymer are melted together, extruded  and milled. If molecules are thermally labile,  then the high temperatures they are exposed  to in processing can be an issue. The benefit  of an amorphous solid dispersion is that the  polymer surrounding the API helps maintain  the state of supersaturation once the dosage  form dissolves, preventing recrystallization or  possible precipitation.

Lipid based formulations come in many  variations, including digestible formulations  and self-emulsifying systems, which are often  commercialized as soft gel capsules. For  digestible lipid formulations, lipid droplets  containing the drug are digested by gastric  and intestinal fluids in the presence of bile salts  and lead to a slower absorption process. For a  self-emulsifying drug delivery system (SEDDS),  the formulation contains surfactants that produce a nano/microemulsion when diluted in  intestinal fluids and can have rapid absorption  as compared to digestible lipid formulations.

The suitability of a digestible formulation can  be assessed by evaluating the API’s solubility  in digestible lipid products versus standard biorelevant media. A lipid approach may impact  how the body will take up the drug, its gut wall permeability, and even promote lymphatic  uptake. Therefore, it is recommended to use in vivo studies to fully evaluate the potential of  the formulation approach.

Image showing what is soft gel capsules

API sparing techniques. When moving  from candidate selection to preformulation/ formulation and in vivo studies, larger amounts  of the API will be needed. Therefore, the more work that is done in earlier phases, the  more efficiently a limited API supply can be  utilized. It can begin by front loading at the  preformulation and formulation selection stages  to decrease reliance on in vivo data. Renejix’s vitro technology screening tools can help  develop optimal formulation with minimal API consumption, as illustrated in FIGURE 4.

Before taking that final step of in vivo studies,  prototypes can be characterized in rank order  to ensure the best candidates progress. One  tool important to these studies is the “Micro”  Dissolution Tool, which utilizes small sample  sizes, making it an ideal tool where API supply  is limited. It provides the ability to analyze  multiple samples with very small amounts of  material using in-situ detection.

Image showing API sparing Techniques

As a case study, let’s examine the use of liquid-liquid phase separation (LLPS) experiments and micro-dissolution to guide formulation  development and prototype selection.

The LLPS assay was used to screen several  polymers and determine their impact on  supersaturation of an API. The results showed  phase separation just before precipitation  would occur. The LLPS data showed the  expected supersaturation concentration of the API to be just under 200 ?g/mL. The  micro-dissolution was conducted over an  extended time to help discriminate between  the polymers investigated. The micro-dissolution results showed that although  the HPMCE3 polymer could achieve and  maintain supersaturation for some time, the  API eventually began to precipitate, so the polymer was ruled out for use in future studies  (FIGURE 5). Another way to adapt the micro-dissolution  apparatus is to look at flux, or the movement  of the drug across a membrane. Using a two-stage dynamic media conversion  of simulated gastric fluid to fasted state  simulating intestinal fluid with pancreatic lipase, the ability of the drug to disperse  from a formulation, stay dissolved, and cross  a simulated membrane, can be examined. In vitro-in vivo correlation experiments  have shown that MicroFLUX data correlates  with in vivo data. Although it may not be  able to predict in vivo exposure, MicroFLUX  experiments can be used to rank the  prototypes and select those that are most  likely to succeed in vivo.

Image showing Oral dosing options

 

Selecting the right dosage form

selecting  the right dosage form by pairing the  formulation technology with the right dosage  form design. Powder-in-a-bottle (PiB) can be  a very simple, flexible approach that can be  dosed as a solution or suspension depending  on attributes of the drug and diluent.

Drug- in-a-capsule is also very simple if the drug is  soluble. For DCS II compounds, a formulated  capsule or tablet, with the assistance of  excipients to help improve the performance  of the API, is preferred. A summary of PiB,  drug-in-capsule (PiC or DiC), and formulated  capsules or tablets as possible oral dosing  options is outlined in FIGURE 6.

Image showing method to select the right dosage form

Renejix’s FormuPhase® Solution Suite platform  uses a science-based approach to identify the  right drug molecule, then pairs it with the right  formulation technology and dosage form to  ensure accelerated path to clinic, with optimal  clinical outcomes for patients (FIGURE 7).

Drug discovery and development can be  a lengthy, costly and risky undertaking. Predictive tools such as the DCS and PBPK  modeling and API-sparing in vitro techniques  can help accelerate the delivery of therapeutics  to clinic. The DCS can help formulators assess  what technology to apply to ensure that the  bioavailability of the drug will be optimally  enhanced. PBPK analysis examines how the drug performs in early animal models,  and helps scientists understand the main  drivers of bioavailability. API-sparing in vitro  formulation characterization tools can help  select the optimal formulation technology  while conserving limited supplies of API. On  their own, these techniques generate useful  data, however, evaluating data from all these tools provides the most benefit. Renejix’s scientists not only have the tools and expertise  to generate and interpret such data, but they  also offer parallel formulation technology  screening and a successful track record of  optimizing thousands of molecules using wide  variety of formulation technologies and dose  forms to help de-risk and accelerate your  early development programs.

Conclusion

Drug discovery and development can be  a lengthy, costly and risky undertaking. Predictive tools such as the DCS and PBPK  modeling and API-sparing in vitro techniques  can help accelerate the delivery of therapeutics  to clinic. The DCS can help formulators assess  what technology to apply to ensure that the  bioavailability of the drug will be optimally  enhanced. PBPK analysis examines how the drug performs in early animal models,  and helps scientists understand the main  drivers of bioavailability. API-sparing in vitro  formulation characterization tools can help  select the optimal formulation technology  while conserving limited supplies of API. On  their own, these techniques generate useful  data, however, evaluating data from all these tools provides the most benefit. Renejix’s scientists not only have the tools and expertise  to generate and interpret such data, but they  also offer parallel formulation technology  screening and a successful track record of  optimizing thousands of molecules using wide  variety of formulation technologies and dose  forms to help de-risk and accelerate your  early development programs.

Image showing a chemical bond

author avatar
Sridhar Gumudavelli
Sridhar Gumudavelli serves as the Vice President of Formulation R&D at Renejix Pharma Solutions, where he brings a wealth of knowledge and experience to the table. His leadership is instrumental in navigating the complex process of drug formulation, leveraging a variety of technologies to enhance drug absorption, bioavailability, and patient compliance.Sridhar’s expertise is not just limited to his hands-on experience; he is also an innovator with several patents filed under his name. These patents reflect his contributions to advancing drug delivery systems, showcasing his ability to tackle some of the most challenging problems in pharmaceutical sciences for the past 30+ years.

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