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Interdependence of biological aspects of the human and physico-chemical principles that governs the preparation and behavior of formulation.
Solubility Lipophilicity/Hydrophilicity Salt for and polymorps Chemical stability particle and powder properties pKa and ionization
Formulation principles Biological principles
Absorption Distribution Metabolism Elimination
Molecular and physicochemical properties impacting oral absorption
Lipinski’s Rule of 5: Veber suggested that polar surfaces Poor absorption/ and molecular permeation may occur flexibility are good if predictor for better MW>500 bioavailability lop P>5 (independent of Hbond donors MW). (-OH, -NH)>5 Increased molecular H-bond acceptors rigidity decreases polarity. (-H, -N)>10
Stereoisomers have similar physicochemical parameters and passive processes. Absorption may be stereospecific when mediated by carrier molecule. Chiral API+ chiral excipient may give stereoselective release mechanism.
The dissolution rate for poor soluble drug according to Noyes-Whitney equation is: dc/dt=[DA/hv]*(Cs-C)
D=diffusion constant H=thickness of diffusion layer A=surface area v=volume of dissolution media Cs=saturated solution concentration C=concentration of drug in solution
Factors governing poor aqueous solubility are: heat of solvation and heat of fusion Solvation energy- Energy associate with dissolving solute in water :evaluated by log P Heat of fusion- additional energy required to liberate molecule from its crystal lattice before it can dissolve (for crystalline compound): evaluated by MP. If high MP and high heat of fusion; then poor solubility. (if heat of fusion is surpassed by heat of solvation, then solubility may change)
Dissociation constant-pKa; intrinsic solubility and salt solubility are determining factors defining solubility profile.
Effect of temperature on solubility
The relationship between solubility and temperature is defined by van’t Hoff’s equation. ln s= ΔH/R(1/T)+ constant
Where s=molar solubility, T=temperature, R=ideal gas constant; ΔH=heat of solvation.
For organic compounds, it has been found that solubility difference between 25 and 37°C are typically about two times. It is most important to study temperature effect for formulation development, particularly for liquid dosage form.
Solubility in gastric and intestinal fluid
Solubility of drug is affected by presence of food and bile salts, lecithin and monooleins. Supersaturation in intestinal fluid is important for compound with poor intrinsic solubility. HPMC enhances absorption of several poor soluble drug. FaSSIF and FeSSIF are used to study realistic impact of solubility on absorption.
Solubility as limiting factor for absorption
According to Lipinski, solubity of LT 10µg/ml will have effect on absorption. MAD=S*Ka*SIWV*SITT; where MAD=maximum
absorbable dose (mg); S=solubility (mg/ml); Ka=absorption rate constant (1/min); SIWC=small intestinal water volume (ml, mostly 250); SITTsmall intestine transit time (min, mostly 270 min)
MAD is concept tool that relates solubility requirement for oral absorption to dose, permeability, GI volume and transit time.
Determination of solubility
Traditional shake flask method. A Powder-XRD run with wet and dry sample gives hydrate information of residual solid. For poorly soluble compound, excess amount of material is added and then vortexing with teflon ball/sonication is done. Amorphous compound can be added to create supersaturation.
Care should be taken to prevent conversion to free form from salt form. If solid salt is not available than in situ salt screening method is used to check solubility. Kinetic solubility is determined by adding compound’s DMSO solution to aq. buffers. It helps to determine poor soluble compounds early. Usefulness and limitation shall be considered.
Prediction of solubility
Yalkowsky and Valvani have introduced a model for nonelectrolytes: Log S=0.5-0.01(MP-25)-log P; where MP is melting point effect for solid phase effect and log P liquid phase effects.
The compound needs to be stable for better shelf-life and bioavailability. For ionizable drug, pH-stabiity profile is important for knowing impact of absorption. The acidic degradation shall also be checked for improving bioavailability. Degradation by hydrolysis, oxidation and reduction. Stability in compound intestine is affected by pH, enzymes, bacterial flora.
Solid state properties
Polymorphism Amorphous material Particle size
Compound may exist in different polymorphic form, solvates or hydrates. Polymorph and pseudo-polymorph have different solubility, crystal shape, dissolution rate and thus possibly different absorption rate. Thermodynamically most stable form shall be selected for dosage form development. Crystallization- re-crystallization are used to determine polymorph, solvates or hydrate form.
Amorphous form has highest free energy having impact on solubility and bioavailability. The pharmaceutical process have impact on product quality. Amorphous form can have 1000 fold solubility, but it is difficult to measure their true solubility as they are not stable in any solvent. If the drug in amorphous form is miscible with polymers in solid dispersion, they may be physically stable even at accelerated condition.
Particle size reduction increases surface area available for dissolution, and thus absorption. At submicron level, particles may agglomerate to reduce the free energy of system which can be prevented by addition of surfactant.
Ionization and pKa
For ionizable compound, the aq. Solubility of ionized species is higher than the unionized species because of higher polarity. Ionizable functional group and magnitude of pKa determines weather the compound will be in ionized form at physiological form.
For transportation of drug, it should be in solution and non-ionized. But non-ionized form have higher lipophilicity, and thus lower solubility. At physiological pH, the drug will be in both ionized and unionized form. The non-ionized spp. will get absorbed and thus it is regenerated for maintenance of equilibrium between ionized-non ionized spp.
Drug must be absorbed across a biological membrane to give a pharmacologic response. Transport across the membrane (Passive/Active) is impacted by ionization equilibria, partitioning into and diffusion across lipophillic membrane along with interaction with transporter system. Lipophilicity affect membrane permeability while solubility affects GI absoprtion.
Passive transport is movement of molecule from higher concentration to lower concentration. It is governed by Fick’s firest law: J=dM/A dt= D(C1-C2)/h, where J=flux, M=drug mass, A=area, t=time, D=diffusion coefficient, C1=drug conc. in intestinal lumen, C2=conc. in blood side
Carrier mediated transport
Depending on the direction and category of solutes, they can also be classified in to uniporter, symporter and antiporter. Based on energy involved, they can be classified in to facilitated diffusion and active transport.
Carrier protein are involved no need of energy. Same as passive diffusion, transport direction of facilitated diffusion depends on solute concentration gradient.
It is energy consuming process. This form of transport involves specific carrier proteins present in the cell membranes. Enzymes, temperature, stereo specificity of molecule can affect it. As this process involves a carrier protein, the mechanism is saturable at high concentrations and uptake via this route can be inhibited by competing substrates.
Drugs can also cross epithelia through gaps (known as gap junctions) between the cells. This route is governed by passive diffusion and small hydrophilic molecules can pass through these gap junctions. Transport across the epithelia can be enhanced using penetration enhancers which can damage the gap junctions; however possible toxicity implications should be considered with such methods.
This process involves internalisation of substances by engulfment by the cell membrane which forms membrane-based vesicles within the cell, known as endosomes. This allows larger molecules or particulates to enter the cell. There are several types of endocytosis: Receptor-mediated endocytosis; Adsorptive endocytosis; Pinocytosis; Phagocytosis
Very small molecules may also be taken up through aqueous pores that are present in some cell membranes. These are ~0.4 nm in diameter so this transport mechanism is very restrictive. Only very small hydrophilic drugs can enter cells via this route.
Substances can also be pushed back out of cells by an energy-dependent efflux system. There are various apical transmembrane proteins which can transport drugs out of the cell. Drugs that are subjected to efflux processes include cytotoxic drugs such as taxol, steroids, immunosuppressants and antibiotics. The genetic information for efflux pumps can be contained within chromosomes and/or plasmids. This allows for the efflux pump genes to be passed to various bacterial species. Expression of several efflux pumps in bacteria can lead to multidrug resistance.
Transporters and Their Substrate
Transporter Substrates Tissue
Lipid transporters/bile acid transporters
Fatty acids, cholesterol, (lipophilic drug?)
Monocarboxylate transporters (organic anionic transporters)
Salicyclic acid, pravastatin, NSAIDs, some fluroquinolones
Organic cation transporters
Epinephrine, choline, dopamine, guanidine, antiarrhythmics, several antihistaminics
Nucleoside analogues used as antiviral and anticancer compounds
Small intestine, kidney
Intestinal dipeptide transporter
β-lactam antibiotics, angiotensin-converting enzyme inhibitors, thrombin inhibitors, thyrotropic-releasing hormone
Amino acid transporters
Gabapentin, baclofen, L-alphamethyl dopa, L-dopa Valproic acid, salicylic acid, penicillins, methotrexate Fosfomycin, phosphonoacetic acid, phosphopropionic acid Etopside, vincristine, paclitaxel, ofloxacin, ciprofloxacin, cyclosporin, peptides, some organic cations, vinblastine
Intestine, kidney, lung
Vitamin transporters Phosphate transporter
Primary factors influencing absorption
Membrane permeability Solubility Dissolution of solid dosage form
Effective permeability (Peff): it is dependent on drug concentration for drugs that absorbs through both passive and active transport.
Fraction of drug absorbed (Fa): permeability through intestinal wall determines fraction of drug absorbed.
Absorption rate constant (Ka): permeability and radius of intestine determines absorption
Permeability absorption model
Physicochemical methods: Lipophilicity (Log P/Log D),
Absorption Potential, Immobilized artificial membranne
In vitro methods:
Animal tissue based methods: Everted Gut technique, Ussing Chamber, Isolated membrane vesicles Cell based methods: caco-2 cells and others, MDCK cells
In situ methods In vivo models In silico methods
Dissolution of solid dosage form
Drug in solid dosage form must be dissolved before it can be absorbed. Factors affecting dissolution affect absorption process for mainly poor soluble, high dose drug. Formulation strategies such as micronization, ionization, surfactants and disintegrants can be used to enhance to increase absorption.
Secondary factors influencing drug absorption
Biological factors of gastro intestinal track
Dosage factors influencing absorption
Gastric emptying time Surface area GI transit time Intestinal motility Food Blood flow Components, volume & properties of GI fluid age
Excipients Coating i.e. enteric coating Surfactants. Etc.
Evaluation of oral drug absorption
Drug absorption assessment using in vivo data
Estimation of fraction of drug absorbed using experimental intestinal permeability in vivo
Peff, human=Q(1-Cout/Cin)/2πRL), where Q=perfusion flow rate, Cin=inlet drug conc. Of perfusion tube, R=radius, L=length
Estimation of MAD using in vivo absorption rate constant and drug solubility
MAD=SKaVT, where S=solubility, Ka=absorption rate constant, V=volume, T=time
Estimation of MAD from drug in vivo permeability in humans and drug solubility
MAD=Peff,humanSAT, where Peff,human=drug permeability in human intestine, S=solubility, A=absorption rate, T=transite time in small intestine
Drug absorption assessment using in vitro data
In vitro testing conditions for determining drug permeability in caco-2 cells and in vitro/in vivo permeability correlation LogPeff, human=constant*LogPeff, caco-2-constant Estimation of fraction of drug absorbed in humans using in vitro drug permeability in caco-2 cells Estimation of MAD in human based on in vitro data MAD=Peff, humanSAeffT, where Aeff=effective surface area without considering villi and microvilli
Correlation of oral bioavailability and intestinal permeability between rat and human
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