Conversely at pH 6. As well as highlighting the caution needed when using these model systems, this work also suggested that careful consideration should be given to the ionisation profiles of research compounds. In a further example, Castro and co-workers 17 produced a series of compounds to address a problem of poor oral absorption in a lead compound. A basic amine group with a p K a value close to 9. Fluorinated analogues were synthesised which lowered the p K a values of the amine to between 8.
Subsequent testing showed that there was a considerable improvement in oral absorption for the fluorinated derivatives. The increase in absorption was attributed to the higher proportion of the neutral species in the gut. Charge state was also highlighted by Martin as an important factor in predicting bioavailability in rats. This was explained in terms of the anionic nature of the membranes used, and was thus rationalised on electrostatic grounds.
Ionisation state only had a minor impact on bioavailability yet acids were found to be more bioavailable on average which was in contrast to acid permeability data in general. His research interestingly concurred with previous studies to show that acids had higher oral bioavailability and was likely to be the result of better solubility and lower clearance.
Simple classification of compounds into acids and bases does not take into account the extent of ionisation which has been considered by previous workers employing p K a values. Clearly, when we consider the nature of membranes and their lipophilic character, the generalisations above regarding non-ionised states and permeability are fully understandable.
Neutral molecules are more readily able to traverse non-polar lipidic membrane environments, unlike charged compounds, where this process is energetically disfavoured.
Despite these studies and the general dogma that the neutral species is greatly favoured in passive transfer across membranes, evidence exists that shows that a proportion of charged molecules are able to be absorbed. In one study, monolayers of Caco-2 cells were used to suggest that ionic species may contribute to overall drug transport. While a drug may be adequately absorbed, other attributes can render it poorly distributed or rapidly cleared, such that it is unable to elicit an adequate pharmacological response.
The parameter, volume of distribution V d , is a theoretical property where large values indicate that a drug is widely distributed, while small values e. Compounds with higher lipophilicity tend to have higher values of V d. More importantly, binding to blood plasma proteins has a significant effect on the volume of distribution. The amount of drug exposed to the liver and the kidney thus varies considerably between acids and bases.
Tissue bound compounds such as bases, tend to form interactions with the acidic head groups of phospho lipids whereas acids will readily bind to lysine residues in blood plasma proteins. A recent study at GlaxoSmithKline 4 concurred with these established findings, demonstrating that basic compounds are more widely distributed throughout the body. Companies involved in new medicines research are interested in the CNS permeability of their research compounds and how well they bind to brain tissue.
Companies developing drugs aimed at CNS targets are aware that the pharmacological response of a compound is directly related to the free fraction in the CNS that is available to bind to the requisite macromolecule. With regard to brain tissue binding, minor differences were found between the binding of acidic, basic, neutral and zwitterionic substances, in contrast to the distinct pattern observed for plasma protein binding.
Instead, brain tissue binding was found to be mostly influenced by non-specific phenomena, especially, lipophilicity. Tight junctions exist between the epithelial cells of the BBB and there are significant populations of efflux pumps to counteract drug entry. Simple models that estimate the extent of penetration of drugs into the CNS are limited by data quality, and as above, most studies segregate compounds into various charge states for research purposes.
Fan et al. Broccatelli et al. Taken together, the information above can be exploited for the design of ligands where CNS penetration is required, or for cases where CNS exclusion is needed to minimise side effects.
There are numerous efflux systems in place to protect the body from harmful substances. A key example is P-glycoprotein P-gp , which is a membrane bound protein residing on the apical surface of the intestinal epithelium and astrocyte membranes of the BBB.
The interest in transporters such as P-gp by the pharmaceutical industry is considerable, as this efflux pump can severely limit the oral absorption of compounds, or counteract access to the CNS. A useful predictive model for P-gp inhibitor affinity has been generated using molecular interaction fields 29 and clear relationships exist between affinity for P-gp and molecular size 4 , 30 as well as the number of hydrogen bond donors.
In the gut, both P-gp and metabolism enzymes are largely co-located performing the same function which is to avoid exposure to unwanted and potentially harmful substances. Ionisation states also play a role, with acids showing lower efflux ratios than neutral and basic compounds, while zwitterions possess higher efflux ratios.
While these findings are important, P-gp affinity for each structural class will vary and laboratory testing is required at an early stage to establish any liabilities. Of major importance to the pharmaceutical industry during drug discovery is the need to avoid compounds that block the hERG potassium channel.
Serious side effects can occur from inhibiting hERG channels, such as QT prolongation, that in severe circumstances can lead to cardiac arrhythmias and death.
Improved models of the hERG channel have been developed recently leading to better predictions of channel affinity. Electrophysiology studies provide a more rigorous assessment than radioligand binding and AstraZeneca tested 7, compounds focussing on both charge state and lipophilicity to develop guidelines for avoiding hERG inhibition.
In agreement with the findings at GSK 4 , basic compounds were found to be more likely to inhibit hERG and this inhibition was also strongly driven by lipophilicity. From ref Phospholipidosis is characterised by excess phospholipids in cells giving them a foamy appearance and is known to be induced by particular compounds that are cationic amphiphiles. While this is a manageable side effect of some drugs, it is troublesome during drug development, as further studies are needed to show that the effects are reversible.
Ploemen and co-workers 37 developed a model to predict the potential for cationic compounds to cause phospholipidosis. This model was later updated 38 to the following simple calculation focussing on both lipophilicity and the p K a of the basic group. Other workers have also sought simple algorithms to predict phospholipidosis.
Using an in vitro model, Tomizawa et al. For more advanced cases of drug development where information on the volume of distribution is available, Hanumegowda and co-workers developed a model that is superior than using p K a and ClogP values alone.
These simple models exploit p K a values to predict compound toxicity and can be easily applied in a drug discovery setting. Based on ClogP and net charge state at pH 4. Impairment of mitochondrial processes has recently been acknowledged as a cause of off-target drug toxicities and has resulted in the withdrawal of several compounds from the clinic.
Two compounds in particular, troglitazone and cerivastatin, were delisted due to their effect on mitochondrial oxidative phosphorylation. Compounds that acutely reduce ATP production result in a range of symptoms such as lactic acidosis which presents clinically as nausea, vomiting and abdominal pain. To prevent these compounds entering animal or human testing, pre-clinical screening methods have been developed to identify molecules that interfere with mitochondrial function.
A number of acidic functional groups were flagged as being particularly problematic such as anthranilic acids, thiazolinediones, fluoromethylsulfonanilides, salicylates and acyclindolones. A consideration of drug clearance needs to encompass both renal and hepatic pathways. There is also a need to include biliary systems and collectively these pathways influence pharmacokinetic parameters such as elimination half-life.
Lipophilicity is a dominant factor in clearance as this determines the membrane permeability of a drug, particularly in renal systems. The aqueous component of blood is filtered by the kidney and reabsorption of compounds is dependent on their logD.
Positive logD 7. Ionisation state plays a role in clearance and is particularly affected by protein binding. As the anionic form of acids can be highly bound to plasma proteins they are less likely to be cleared, whereas bases tend to show higher clearance rates.
Secondary metabolism also has to be considered as initial metabolism can often generate ionisable functional groups. For example, carboxylic acid containing compounds are liable to acyl-glucuronidation which influences their chemical reactivity and side effect profile.
Since lipophilic compounds are reabsorbed in the kidneys, metabolism is required to render them more water soluble. Drugs and other exogenous chemicals are often metabolised by cytochrome P enzymes, with the majority of drugs being metabolised by the cytochrome P isoforms 1A2, 2C9, 2C19, 2D6 and 3A4.
The reasons for this relate to reducing the production of potentially toxic metabolites and to avoid interfering with the metabolism of other drugs which can lead to drug interactions. Reducing the metabolism of a drug also allows for longer half-lives and less frequent dosing schedules. The P isoforms most influenced by charge state include 2C9 and 2D6, while for the remaining isoforms, ionisation state was shown to play a lesser role.
Cytochrome P enzymes and other drug metabolising enzymes may yield biologically active metabolites, a process known as bioactivation. Fortunately, 3D protein structural information is beginning to help us appreciate substrate preferences although these enzymes are notoriously promiscuous.
This is understandable remembering their broad role in metabolising both endogenous and exogenous compounds. The first of our studies looked at a set of published p K a values for a series of older drugs see ref 7. While this was informative, a broader set was subsequently investigated comprising compounds in current clinical use.
Furthermore, the compounds were split into oral drugs and those that target the CNS to allow comparisons to be made between these groups.
Surveys of this nature give insights into drugs in general and the observations have the potential to be applied in early stage discovery work. Focussing on oral drugs showed that The large proportion of ionisable compounds was an interesting statistic that is a reflection of the optimisation process that provides the necessary properties suitable for binding site interactions and biopharmaceutical properties.
A , Proportion of compound categories for ionisable oral drugs. Acids with p K a values above 10 or bases with p K a values below 0. The remaining ionisable compounds acid p K a range and base p K a range were divided into the following groups: single acid-containing substances, single base-containing substances, compounds with two acidic groups, compounds with two basic groups, simple ampholytes one acidic and one basic group and other complex combinations of acidic and basic groups complex ampholytes.
The histogram column heights are expressed as a percentage. Plots of the p K a distributions of single acid and single base containing substances are shown in Figures 3B and 3C. Interestingly for the acids, there is a biphasic distribution showing a paucity of acids with p K a values between 6 and 7. This can be explained by the predominance of carboxylate and phenolic substances in this set and the range of p K a values usually encountered for these groups.
The bases on the other hand have a distribution showing that most of these substances had p K a values above 6. Once again, this can be explained by the large number of aliphatic amines in this set that mostly target GPCRs. The overall makeup of the compound classes and p K a distributions is influenced by numerous factors.
The value of this work was to provide additional information beyond standard physicochemical properties that may influence the choice of screening collections and the diversity of ionisable functional groups within these compounds. Our analysis of screening compounds and chemogenomics datasets complements this work on drugs and a manuscript on this topic is in preparation. Other groups have also considered the charge states of drugs which has been included in their overall analyses of physicochemical properties.
Their study culminated in a set of observations that could predict whether a carboxylic acid containing compound would show reasonable ADME properties.
A more extensive analysis of molecular properties and charge states was conducted by Leeson and co-workers 6 who also examined changes to these parameters over the past few decades. A wide range of properties were compared looking for trends to determine whether particular characteristics had reached consensus over time. For example, lipophilicity was shown to be increasing for neutral and acidic oral drugs over time, while basic drugs have already reached a lipophilicity range common to the other classes.
Other findings showed that 6 :. Importance of Solubility Oral ingestion is the most convenient and commonly employed route of drug delivery due to its ease of administration, high patient compliance, costeffectiveness, least sterility constraints, and flexibility in the design of dosage form.
Techniques for Solubility Enhancement Solubility improvement techniques can be categorized in to physical modification, chemical modifications of the drug substance, and other techniques. Physical Modifications — Particle size reduction like micronization and nanosuspension, modification of the crystal habit like polymorphs, amorphous form and cocrystallization, drug dispersion in carriers like eutectic mixtures, solid dispersions, solid solutions and cryogenic techniques.
Chemical Modifications — Change of ph, use of buffer, derivatization, complexation, and salt formation. Miscellaneous Methods — Supercritical fluid process, use of adjuvant like surfactant, solubilizers, cosolvency, hydrotrophy, and novel excipients.
Particle Size Reduction The solubility of drug is often intrinsically related to drug particle size; as a particle becomes smaller, the surface area to volume ratio increases. Solid Dispersion The concept of solid dispersions was originally proposed by Sekiguchi and Obi, who investigated the generation and dissolution performance of eutectic melts of a sulfonamide drug and a water-soluble carrier in the early s [ 18 ].
Hot-Melt Method Fusion Method The main advantages of this direct melting method is its simplicity and economy. Solvent Evaporation Method Tachibana and Nakamura [ 23 ] were the first to dissolve both the drug and the carrier in a common solvent and then evaporate the solvent under vacuum to produce a solid solution.
Hot-Melt Extrusion Hot-melt extrusion is essentially the same as the fusion method except that intense mixing of the components is induced by the extruder. Nanosuspension Nanosuspension technology has been developed as a promising candidate for efficient delivery of hydrophobic drugs. Precipitation Technique In precipitation technique the drug is dissolved in a solvent, which is then added to antisolvent to precipitate the crystals. Media Milling The nanosuspensions are prepared by using high-shear media mills.
High Pressure Homogenization High-pressure homogenization has been used to prepare nanosuspension of many poorly water soluble drugs. Combined Precipitation and Homogenization The precipitated drug nanoparticles have a tendency to continue crystal growth to the size of microcrystals. Supercritical Fluid SCF Process Another novel nanosizing and solubilisation technology whose application has increased in recent years is particle size reduction via supercritical fluid SCF processes.
Cryogenic Techniques Cryogenic techniques have been developed to enhance the dissolution rate of drugs by creating nanostructured amorphous drug particles with high degree of porosity at very low-temperature conditions.
Spray Freezing onto Cryogenic Fluids Briggs and Maxvell invented the process of spray freezing onto cryogenic fluids. Spray Freezing into Cryogenic Liquids SFL The SFL particle engineering technology has been used to produce amorphous nanostructured aggregates of drug powder with high surface area and good wettability.
Ultra-Rapid Freezing URF Ultra-rapid freezing is a novel cryogenic technology that creates nanostructured drug particles with greatly enhanced surface area and desired surface morphology by using solid cryogenic substances.
Inclusion Complex Formation-Based Techniques Among all the solubility enhancement techniques, inclusion complex formation technique has been employed more precisely to improve the aqueous solubility, dissolution rate, and bioavailability of poorly water soluble drugs. Figure 1. Figure 2. Kneading Method This method is based on impregnating the CDs with little amount of water or hydroalcoholic solutions to convert into a paste.
Microwave Irradiation Method This technique involves the microwave irradiation reaction between drug and complexing agent using a microwave oven. Micellar Solubilization The use of surfactants to improve the dissolution performance of poorly soluble drug products is probably the basic, primary, and the oldest method. Hydrotrophy Hydrotrophy is a solubilisation process, whereby addition of a large amount of second solute, the hydrotropic agent results in an increase in the aqueous solubility of first solute.
Crystal Engineering The surface area of drug available for dissolution is dependent on its particle size and ability to be wetted by luminal fluids. Conclusion Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs and solubility is the basic requirement for the absorption of the drug from GIT. References 1. Clugston M, Fleming R. Advanced Chemistry. Oxford, UK: Oxford Publishing; Solubilization of drugs in aqueous media.
In: Swarbrick J, editor. Encyclopedia of Pharmaceutical Technology. Martin A. Solubility and Distribution Phenomena. Lippincott Williams and Wilkins; Physical Pharmacy and Pharmaceutical Sciences. IUPAC gold book. Aulton M. Dissolution and solubility. In: Aulton ME, editor. Pharmaceutics: The Science of Dosage form Design. Churchill Livingstone; British Pharmacopoeia, A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.
Pharmaceutical Research. Yellela SRK. Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. Edward KH, Li D.
Elsevier; Solubility; p. Solubility enhancement techniques. Solubility enhancement—eminent role in poorly soluble drugs. Research Journal of Pharmacy and Technology. Review on solubility enhancement techniques for hydrophobic drugs. Pharmacie Globale. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Advanced Drug Delivery Reviews. Dissolution enhancement of fenofibrate by micronization, cogrinding and spray-drying: comparison with commercial preparations.
European Journal of Pharmaceutics and Biopharmaceutics. Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods and Findings in Experimental and Clinical Pharmacology.
Sekiguchi K, Obi N. Studies on absorption of eutectic mixtures. Chemical and Pharmaceutical Bulletin. Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective.
Preparation and in vitro evaluation of solid dispersions of halofantrine. International Journal of Pharmaceutics. Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir.
Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. Journal of Pharmaceutical Sciences. Tachibana T, Nakamura A. Colloid and Polymer Science. Nanosuspension drug delivery technology and application—nanotech—express pharma pulse.
Nanosuspensions for the formulation of poorly soluble drugs. Pharmaceutical Emulsion and Suspension. Nash RA. Novel drug delivery technologies for insoluble drugs. Indian Drugs. Nanosuspensions: a promising drug delivery strategy.
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Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Nanosuspension formulations for low-soluble drugs: pharmacokinetic evaluation using spironolactone as model compound.
Drug Development and Industrial Pharmacy. Production and characterization of a budesonide nanosuspension for pulmonary administration. Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology. Sunkara G, Kompella UB. Drug delivery applications of supercritical fluid technology. Drug Delivery Technology. Journal of Supercritical Fluids.
Leuenberger H. Spray freeze-drying—the process of choice for low water soluble drugs? Journal of Nanoparticle Research. Mumenthaler M, Leuenberger H. Atmospheric spray-freeze drying: a suitable alternative in freeze-drying technology. Williams RQ. Process for production of nanoparticles and microparticles by spray freezing into liquid. US Patent no. Process for preparing powder blends. A novel particle engineering technology: spray-freezing into liquid. Process and apparatus for freezing a liquid medium.
Cyclodextrins in pharmaceuticals: an overview. Rapidly dissolving repaglinide powders producers by the ultra-rapid freezing process. Cyclodextrin drug carrier systems. Chemical Reviews. Dissolution enhancement of nimesulide using complexation and salt formation techniques. The physicochemical characteristics of freeze-dried scutellarin- cyclodextrin tetracomponent complexes.
Journal of Pharmaceutical and Biomedical Analysis. Physical Pharmacy. Micellar solubilization of drugs. Journal of Pharmacy and Pharmaceutical Sciences. Micellar solubilization of some poorly soluble antidiabetic drugs. Solubility enhancement of some water-insoluble drugs in the presence of nicotinamide and related compounds. The solubility of benzodiazepines in sodium salicylate solution and a proposed mechanism for hydrotropic solubilization. Functions of hydrotropes sodium salicylate, proline, pyrogallol, resorcinol and urea in solution with special reference to amphiphile behaviors.
Colloids and Surfaces A. Pharmaceutical overview of spherical crystallization. Der Pharmacia Lettre. In pharmaceutical formulation for other applications, it is important to avoid large changes in the osmotic pressure across a cellular membrane. Thus, when buffered isotonic solutions are made for eyes, soft tissues, nasal cavities, and anal or vaginal cavity applications, special considerations of isotonicity arise to avoid complications.
A buffered isotonic solution is prepared and administered that will have the same solute concentration as that in the biological fluid it contacts. Most buffers in pharmacy are manufactured by companies such as Baxter and Abbott Laboratories. However, many occasions still arise in the pharmacy to calculate and prepare isotonic buffer solutions 2. Pharmacists must draw on their knowledge of anatomy, physiology, mathematics, chemistry and other sciences to prepare the appropriate admixture for beneficial patient outcomes.
Ken Appelt is a senior sales and marketing executive with experience that includes product design, research, production, quality assurance, distribution and education. He has been writing and publishing articles in since , mainly in healthcare, medical device and scientific periodicals. Monitor the health of your community here. More Articles.
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