OUR FORMULATION TECHNOLOGIES
OUR FORMULATION TECHNOLOGIES
harnessing the FORMULATION principles that have stood the test of time
FORMULATION TECHNOLOGIES
harnessing the FORMULATION principles that have stood the test of time
For ionizable APIs, modifying solution pH provides an effective way of increasing the proportion of compound that is present in the ionized form. In turn, increasing ionization increases polarity and therefore increases API solubility in polar (aqueous) solutions.
Salt formation results in a similar endpoint, and in many ways salts of weak acids and bases are the solid-state equivalent of pH adjustment. Salts are formed via an ionic interaction between weakly acidic or basic APIs and an oppositely charged basic or acidic counterion. When salts are subsequently allowed to dissolve and dissociate in water, the acidic or basic counterion from which they were derived causes a shift in the pH of the solution to provide an effect similar to that obtained by pH adjustment. Isolation of APIs as a particular salt form also changes the nature of the crystal lattice, resulting in differences in dissolution rate from alterations in solid-state properties compared with the free acid or free base form.
Salt formation results in a similar endpoint, and in many ways salts of weak acids and bases are the solid-state equivalent of pH adjustment. Salts are formed via an ionic interaction between weakly acidic or basic APIs and an oppositely charged basic or acidic counterion. When salts are subsequently allowed to dissolve and dissociate in water, the acidic or basic counterion from which they were derived causes a shift in the pH of the solution to provide an effect similar to that obtained by pH adjustment. Isolation of APIs as a particular salt form also changes the nature of the crystal lattice, resulting in differences in dissolution rate from alterations in solid-state properties compared with the free acid or free base form.
SALTS & pH ADJUSTMENT
Solubilization refers to the process of increasing the solubility of a poorly soluble compound via incorporation in surfactant micelles. The lipophilic micelle core provides a nonpolar reservoir into which highly lipophilic compounds may partition, enhancing apparent aqueous solubility.
Surfactants are often combined with cosolvents, to increase API loading in the formulation and to reduce the extent of precipitation as cosolvent-rich formulations are diluted in vivo.
Surfactant/cosolvent-based formulations are simple and effective and we often propose them for formulation of moderately insoluble compounds in preclinical and early clinical studies.
Surfactants are often combined with cosolvents, to increase API loading in the formulation and to reduce the extent of precipitation as cosolvent-rich formulations are diluted in vivo.
Surfactant/cosolvent-based formulations are simple and effective and we often propose them for formulation of moderately insoluble compounds in preclinical and early clinical studies.
SOLUBILIZATION
Cyclodextrins (CDs) are macrocyclic oligosaccharides consisting of a hydrophilic outer exterior and a hydrophobic inner cavity. API molecules are able to form dynamic inclusion complexes within this cavity, and the higher solubility of the API-CD complex relative to the solubility of API alone increases apparent solubility, often over several orders of magnitude.
The nature of the API-CD complex dictates that solubilization with CDs is molecule-specific and driven by the relative “fit” of the molecule (or a portion of the molecule) within the CD cavity. CD approaches are therefore less generic than solubility enhancement strategies such as micellar solubilization. Nonetheless, CDs solubilize a wide variety of structurally distinct compounds, both neutral and ionized, and may be used with other solubilization strategies, such as pH adjustment.
The nature of the API-CD complex dictates that solubilization with CDs is molecule-specific and driven by the relative “fit” of the molecule (or a portion of the molecule) within the CD cavity. CD approaches are therefore less generic than solubility enhancement strategies such as micellar solubilization. Nonetheless, CDs solubilize a wide variety of structurally distinct compounds, both neutral and ionized, and may be used with other solubilization strategies, such as pH adjustment.
CYCLODEXTRIN COMPLEXATION
Reducing particle size in the submicron range leads to a dramatic increase in the surface area available for solvation and an increase in the rate of dissolution for solid compounds. Particles in the nanoscale may also be more soluble because of changes to particle curvature and the introduction of defects into the crystal lattice. As a result, API nanocrystals may yield oral bioavailabilities that far exceed those obtained using conventional particles or micronized particles of poorly water-soluble compounds.
At Harpago, we utilize top-down particle size reduction processes, where larger particles are fragmented into smaller ones via wet milling techniques, to produce so-called nanosuspensions.
A critical component of nanosuspenion development resides in the inhibition of particle growth via crystal growth (Ostwald ripening) or aggregation effects. This may be accomplished via the judicious addition of suspension stabilizers, typically polymers, surfactants or combinations of both. We meticulously probe this particle growth risk via a combination of analytical techniques.
Nanosuspensions provide a flexible approach to oral and parenteral administration and can be used as liquid forms preclinically and early clinically. For late-phase or commercial use, nanosuspensions may be converted into solid forms after removal of water (for example via spray drying or bead layering) and subsequently processed into a capsule or a tablet formulation.
Contact us if you want to find out whether a nanosuspension is the right formulation approach for your compound.
At Harpago, we utilize top-down particle size reduction processes, where larger particles are fragmented into smaller ones via wet milling techniques, to produce so-called nanosuspensions.
A critical component of nanosuspenion development resides in the inhibition of particle growth via crystal growth (Ostwald ripening) or aggregation effects. This may be accomplished via the judicious addition of suspension stabilizers, typically polymers, surfactants or combinations of both. We meticulously probe this particle growth risk via a combination of analytical techniques.
Nanosuspensions provide a flexible approach to oral and parenteral administration and can be used as liquid forms preclinically and early clinically. For late-phase or commercial use, nanosuspensions may be converted into solid forms after removal of water (for example via spray drying or bead layering) and subsequently processed into a capsule or a tablet formulation.
Contact us if you want to find out whether a nanosuspension is the right formulation approach for your compound.
NANOSUSPENSIONS
Lipid-based formulations (LBFs) are a special type of solubilized formulation that comprise a relatively large concentration of (water-immiscible) lipid. LBFs are an especially attractive option for the formulation of compounds with high log P and relatively low melting point.
The advantage of including a lipid in a formulation is that lipid will disperse on contact with the aqueous fluids of the gastrointestinal tract into a coarse or finely divided emulsion. This dispersed lipid phase has the ability to sequester lipophilic APIs, which dramatically reduces the risk of recrystallization of API in the gastrointestinal fluids.
On entry into the small intestine, the presence of lipid triggers the physiological mechanisms responsible for digestion of dietary lipids (secretion of bile salts, phospholipids and lipases), leading to digestion of the lipid emulsion droplets into finer colloidal structures from which absorption may occur.
LBFs may be dosed as liquids in preclinical and early clinical development, and are typically formulated as liquid-filled capsules for late-phase and commercial use.
Our customers are often in search of self-emulsifying lipid formulations, the so-called SMEDDS and SNEDDS. Read here how we feel about using these types of formulations.
The advantage of including a lipid in a formulation is that lipid will disperse on contact with the aqueous fluids of the gastrointestinal tract into a coarse or finely divided emulsion. This dispersed lipid phase has the ability to sequester lipophilic APIs, which dramatically reduces the risk of recrystallization of API in the gastrointestinal fluids.
On entry into the small intestine, the presence of lipid triggers the physiological mechanisms responsible for digestion of dietary lipids (secretion of bile salts, phospholipids and lipases), leading to digestion of the lipid emulsion droplets into finer colloidal structures from which absorption may occur.
LBFs may be dosed as liquids in preclinical and early clinical development, and are typically formulated as liquid-filled capsules for late-phase and commercial use.
Our customers are often in search of self-emulsifying lipid formulations, the so-called SMEDDS and SNEDDS. Read here how we feel about using these types of formulations.
LIPID-BASED FORMULATIONS
Amorphous solid dispersions (ASDs) increase API dissolution via several mechanisms, including a reduction in effective particle size, improved wetting, enhanced solubilization, and elimination of the impact of crystal lattice energy via stabilization of API in the more soluble amorphous state. The mechanism of dissolution enhancement is largely dictated by the structure of the solid dispersion formed, but it is underpinned in many cases by the fundamental differences in solubility and dissolution behavior of a crystal and a glass of the same material. The bioavailability-enhancing effect of ASDs is also critically dependent on the colloidal phase that is formed after formulation hydration in vivo.
ASDs are a widely sought-after formulation technology, as they are often the only formulation option for the high-log P, high-melting point new chemical entities that emerge from today's discovery pipelines such as kinase inhibitors and protein degraders.
While intrinsically a potent formulation approach, ASDs introduce a physical stability risk that is not seen with most other formulation approaches. The API dispersed in the polymer matrix is at great risk of converting back to an energetically more favorable crystalline form during storage, manufacture and upon hydration in vivo. We devote a great deal of our development efforts to selecting polymers that will interact favorably with the API to prevent recrystallization from happening. All formulations designed are critically evaluated via a combination of state-of-the-art solid-state analysis techniques such as (high-resolution)-XRPD, DSC, FT-IR and TG-MS.
Our preferred technique to manufacture ASDs during formulation screening and for clinical production is spray-drying, as this technology offers a number of advantages in early development (notably low API consumption) and is applicable to APIs of great chemical diversity.
ASDs are a widely sought-after formulation technology, as they are often the only formulation option for the high-log P, high-melting point new chemical entities that emerge from today's discovery pipelines such as kinase inhibitors and protein degraders.
While intrinsically a potent formulation approach, ASDs introduce a physical stability risk that is not seen with most other formulation approaches. The API dispersed in the polymer matrix is at great risk of converting back to an energetically more favorable crystalline form during storage, manufacture and upon hydration in vivo. We devote a great deal of our development efforts to selecting polymers that will interact favorably with the API to prevent recrystallization from happening. All formulations designed are critically evaluated via a combination of state-of-the-art solid-state analysis techniques such as (high-resolution)-XRPD, DSC, FT-IR and TG-MS.
Our preferred technique to manufacture ASDs during formulation screening and for clinical production is spray-drying, as this technology offers a number of advantages in early development (notably low API consumption) and is applicable to APIs of great chemical diversity.
AMORPHOUS
SOLID DISPERSIONS
SOLID DISPERSIONS
