The weak base is absorbed at a faster rate from the intestine (pH 7.50 - 8), this is because the basic substances can't be ionized in basic medium. So the uncharged substances can be passed easily due to its lipid solubility. So, in this case pH = pKa. Hence, when pH is equal to pKa, the drug is ionized halfly Increase in ionization intensiﬁes a drug's water solubility and decreases its liposolubility. In general, drugs cross cellular membranes in undissociated forms as intact molecules and act in dissociated forms as ions. The liposolubiltiy is affected by pH of the environmental medium and by the degree of dissociation pKa. Usually, drugs. C) pKa value and state of ionization: Non-ionised drugs are better absorbed than ionized drugs depending upon the surrounding ph and pKa value of the drug. D) Partition Coefficient: It is the ratio of solubility of the drug in a non-aqueous solvent to the ratio of solubility of the drug in an aqueous solvent PHYSICOCHEMICAL FACTORS AFFECTING DRUG ABSORPTION. 1) Drug solubility & dissolution rate. 2) Particle Size and Effective Surface Area of the Drug. 3) Polymorphism and Amorphism. 4) Hydrates/Solvates (Pseudopolymorphism) 5) Salt form of the drug. 6) Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis
2) A basic drug with a pKa of 7.8 is a known teratogen. See the example below: In this example, 72% of the drug is ionized which means 28% of the drug is unionized and will pass through the placenta to effect the baby But, many uncharged drugs can't be absorbed or they are insufficiently lipid soluble like aminoglycosides. This is because of occurrence of H - bond which converts the uncharged molecules to hydrophilic. For ionization of weak base, BH+ <===> B + H+. By Handerson - Hasselbach equation, pH = pKa + log10 [B]/ [BH+] So solubility & Pka presentation 1. PRAPARED BY:- MAYURI SAWANT First Year M.Pharm 1 2. DEFINATION:-It is investigation of physical and chemical property of drug substance alone & or when combined with excipient. OBJECTIVE: To generate information useful to formulator in devoloping Stable & safe dosage form with good bioavailability. Name Phenylephrine hydrochloride Drug Entry Phenylephrine. Phenylephrine is an alpha-1 adrenergic receptor agonist used to treat hypotension, 6,8 dilate the pupil, 7 and induce local vasoconstriction. 1 The action of phenylephrine, or neo-synephrine, was first described in literature in the 1930s. 2 Phenylephrine was granted FDA approval in 1939. The solubility of a drug is defined as the maxi-mum quantity of a drug dissolved in a given volume of a solvent at chosen temperature, pressure and pH. For ionizable drugs, the solubility can be affected by the pH of the solution, and the intrinsic solubility (S0) is defined as the concentration of a saturated solution of the neutral form of the drug, in equilibrium with its solid at constant temperature and pressure
solution, lipid solubility and degree of ionization influence absorption. It should not be assumed that the IM route is as reliable as the IV route. 5. Subcutaneous injection Some drugs, notably insulin, are routinely administered SC. Drug absorption is generally slower SC than IM, due to poorer vascularity The degree of ionization (pKa) of a drug is a unique physicochemical property that controls its ionization state when in solution. If the drug's p Ka is the same as the pH of the solution it is dissolved in, then 50% of the drug exists ionized and 50% exists nonionized. As the pH of the solution changes, the state of ionization changes as well Drugs that have poor aqueous solubility have a slower drug absorption rate, which can lead to inadequate and variable bioavailability, and render the drug ineffective. 4 Factors Affecting Solubility pH Levels — pH measures the amount of hydrogen content in a solution—the more hydrogen ions, the lower the pH and vice versa
Partition coefficient (Log P), distribution coefficient (Log D), Ionization constant (pKa) and pH solubility, the important components of inherent properties of drug substances and inactive ingredients, can determine the physicochemical properties, quality and potency of the end products intrinsic solubility and pKa is the negative logarithm of the ionization constant of the molecule. The HH relationship can be used to predict the pH-dependent aqueous solubility of drugs when the pKa and logS 0 values of the compound are known. It is frequently used in orde
Drug solubility is an important aspect of drug development. The objective of this investigation was to measure solubilities of five drugs (cimetidine, phenylbutazone, fenbufen, nitrofurantoin, triamterene) at constant pH in range of temperature from 270 to 340 K in three solvents: water, ethanol and 1-octanol with the dynamic-visual method and the saturation shake-flask method using. Dissolution, lipid solubility, ionization state (pKa) and transporters all affect net diffusion through the intestinal membranes and overall bioavailability to the systemic circulation. Distribution: Drugs are distributed into various compartments in the body where they find targets and metabolic enzymes The calculations of the macroscopic pKa of antiangiogenic drugs investigated were performed using the program AB/pKa module implemented in the VCCLAB program . Lipophilicity and water solubility calculations were carried out using web-based VCCLAB software [25, 26] Water/Lipid Solubility Case (p. 47) Structural feature in Meclizine Physical property Aromatic hydrocarbon Hydrophobic in the stomach (pKa=10.5; the pH of the environment is less than the pKa of the basic drug, therefore the functional group will be ionized). At pH=3.5, the guanidine group will still be ionized (same rationale) The relationship between the molar solubility of a drug in water, S w, at a temperature T (in kelvins), and the melting point T m, for a non-ideal solution may be written as where is the entropy of fusion (melting), γ is the activity coefficient and is the molar volume of the solvent. Equation (4.2) shows an increase of solubility as the melting point decreases
For Acidic drug pH= pKa+log [(S-S0)/S0] S=Over all solubility of substance For basic drug So=solubility of unionized species Solubility of drug is largely due to, 1. Polarity of the solvents, that is, to its dipole moment. A polar solvent dissolves ionic solutes and other polar substances 2. The ability of solute to form hydrogen bond with.
pKa of drug The lipid solubility of the unionized drug pH at the absorption site. a) pKa of drug Amount of drug that exist in unionized form and in ionized form is a function of pKa of drug & pH of the fluid at the absorption site and it can be determined by Henderson-hesselbach equation: A drug that can be efficiently solubilized by pH control should be either weak acid with a low pKa or a weak base with a high pKa. Similar to the lack of effect of heat on the solubility of non-polar substances, there is little effect of pH on nonionizable substances Solubility of drugs by Abhijit Debnath - issuu. W. Physical Pharmaceutics-I. temperature is constant, the solubility of the gas corresponds to its partial pressure. Consider the following formula. Drug/CD complexes, especially those of the natural CDs, have tendency to self-assemble in aqueous solutions to form aggregates (Figure 1).At elevated CD concentrations these aggregates can become large and precipitate as solid microparticles .In addition, the natural CDs and their complexes have limited solubility in aqueous solutions
pKa value of 8.4; however, it has limited solubility. One important pharmaceutical property for this drug that needed to be addressed was improving its aqueous solubility. Due to the acidic nature of the drug, basic counterions with pKa values >10.4 were likely to form pharmaceutically acceptable salts The measurement of pK a and log P. The pK a is the pH at which the molecule is 50% protonated. Log P (or partition co-efficient) is a measure of the lipophilicity of a compound. Cyprotex's pK a and log P determination uses UV-metric and pH-metric technology developed by Sirius. This is considered to be a 'gold standard' method for. Solubility of Drugs. 3. Exercise 1.2 Calculate molality of a solution containing 4.0 g NaCl dissolved in 20.0 g :vater. Solution: (i) mole of solute= mass / molar mass molar mass = 22.99 + 35.45.
The dissociation constant (pka) of the drug. 2. The lipid solubility of the unionized drug ( a function of drug KO/W). 3. The pH at the absorption site. • Brodie proposed the pH partition theory to explain the influence of GI pH and drug pka on the extent of drug transfer or drug absorption. • Ph partition theory of drug absorption is based. .0 and 8.0. A drug substance is considered highly solubl Naloxone is a synthetic morphinane alkaloid that is morphinone in which the enone double bond has been reduced to a single bond, the hydrogen at position 14 has been replaced by a hydroxy group, and the methyl group attached to the nitrogen has been replaced by an allyl group. A specific opioid antagonist, it is used (commonly as its hydrochloride salt) to reverse the effects of opioids, both. Thus, the generalization that cationic each study was substance specific, with solubility values drugs display a solubility range of 3 log units in mono- determined at pH values corresponding to the uncharged valent buffers (Avdeef, 2001, 2003), was not applicable to species, the pKa -value and in the close interval 2-3 log units pH.
liquid oral or parenteral.Fundamental preformulation properties include - Solubility, dissociation constant (pKa), salt formation, partition or distribution coefficient, pH solubility profile and dissolution kinetics, permeability, soli Absorption: Absorption is the process by which drug molecules cross biological membranes. It is usually associated with oral drugs and their absorption through the GIT. It also occurs by subcutaneous, intra muscular and transdermal routes of administration of drugs.However, the absorptive process does not occur during direct injection of drug by intravenous or intra arterial injection Drug pKa and solubility. As mentioned, the ionization of the drug affects its transportation across the cell membrane. The amount of the ionized form present depends on the environmental pH (of the stomach, for example) and the pKa of the drug The pKa is the pH value at which a chemical species will accept or donate a proton. The lower the pKa, the stronger the acid and the greater the ability to donate a proton in aqueous solution. The Henderson-Hasselbalch equation relates pKa and pH. However, it is only an approximation and should not be used for concentrated solutions or for. .42 and its aqueous solubility is of 61.7 mg/L or 1 part in ~16,000 . Therefore, propranolol should be considered to be a low solubility drug
than pKa of weakly-acidic drugs increases the solubility of that drug, those excipients which act as alkalizing agents may increase the solubility of weakly basic drugs [14,15]. After pH adjustment, ionisable compounds (may be acids or bases or zwitter ionic) are stable and soluble. It can also be applied to crystalline as well as lipophillic. Doxorubicin is an anthracycline antibiotic with antineoplastic activity. Doxorubicin, isolated from the bacterium Streptomyces peucetius var. caesius, is the hydroxylated congener of daunorubicin.Doxorubicin intercalates between base pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis
For drugs which are weak acids or bases the pKa of the drug and the pH of the GI tract fluid and the pH of the blood stream will control the solubility of the drug and thereby the rate of absorption through the membranes, lining the GI tract. Brodie et al. (in 1957) proposed the pH - partition theory to explain the influence of GI pH and drug. drugs or lower for basic drugs than the pKa of dissolved drug will increase the dissociation (ionization) of the drugs to 90%, while a 2 pH unit differences from the pKa value will increase the ionization to 99.9%. Therefore, the larger the pH differences between the pKa of a drug and pH of the solvent, the larger the ionization Poorly soluble drugs are problem in pharmaceutical formulations, poor solubility, making them poor candidates as new drugs. And about 40% drugs from newly developed chemical entities are lipophilic in nature and fail to reach market due to poor water solubility. The poor solubility of drugs remains one of the most challenging aspects i
Keywords:Ionization, lipophilicity, pKa, LogP, solubility, biopharmaceutics, supersaturation, precipitation. Abstract: Ionization, lipophilicity and solubility have a profound influence on the transport properties of drug molecules. We will present an overview of why physicochemical properties are important, before discussing how the properties. . Cyprotex's Turbidimetric Solubility assay investigates the kinetic solubility of compounds by diluting a test compound solution prepared in DMSO into aqueous buffer. Turbidimetry is used as the end-point by measuring absorbance at 620 nm
The solubility of acidic compounds increases as the pH of the solution is increased (above the pKa) and the solubility of basic compounds increases as the pH is lowered below the pKa. macro pKa The log P should be calculated at pH where the drug is in neutral/un-ionized form. pKa 4.8 10.9 Key drug properties impacting dissolution include acid/base character, pKa, intrinsic solubility, and lipophilicity 9, 20-22. Key formulation properties include the presence of acidic or basic excipients and their pKa values, and the presence of polymers with the tendency to swell 23, 24 LogP and logD are measures of lipophilicity. Lipophilicity is a key parameter in understanding the pharmacokinetic behaviour of drugs and can influence distribution into tissues, absorption and protein binding characteristics of a drug, as well as being an important factor in determining the solubility of a compound a on Aqueous Solubility Aqueous solubility of an ionisable compound is highly pH dependent The dependent. The ioni edionised fo m i ll mo e form is usually more sol ble th oluble, thus solubility increases with percentage ionised: 100 Diclofenac - pK a 4.08 (acidic) n t Ionised 50 Perce 0 pH 2468 10 pH 3 pH 5 pH 7.4 pH 9 17 uM >350 uM >350 uM.
cations introduced by poor sample solubility and overlapping pKa values. High-Throughput Measurement of Drug pKa Values for ADME Screening John Comer, Karl Box* Keywords: ionization constant, drug absorption, ADME *Correspondence Sirius Analytical Instruments Ltd. Riverside, Forest Row Business Park Forest Row, East Sussex RH18 5DW United Kingdo • With a pKa of 5.2, the drug has to be buffered near pH 4 to obtain more than 90% ionization. 39 Adjustments in pH to maintain water solubility can sometimes lead to chemicalstabilityproblems. An example is indomethacin(HA acid; pKa 4.5), which is unstable in alkaline media. Therefore, th The solubility of non-ionizable compounds is a single value that reflects a simple balance between the molar free energy of the solid drug and that of the drug interacting with a polar aqueous solvent; for an ionizable drug, however, the ionizability of both the drug and the solvent must be considered Aggregation and micelle formation of drugs in a saturated solution can complicate the interpretation of the solubility measurements, especially when the molecules are ionizable. There are many reports of such systems [1-6]. For example, doxycycline , with intrinsic solubility S 0 = 0.72 mg/mL, at 25 oC in 1 It is possible that the solubility is compatible with absorption of the human dose, but it may not be possible to pH solubility profile of compound with pKa = 8.9. pH solubility profile of compound with pKa = 8.9. 0 2 4 6 8 10 12. Figure 9.6. Solubility profile of a basic compound withpKa = 8.9. 0 2 4 6 8 10 12. Figure 9.6
Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory Class 1 - High Solubility, High fraction absorbed Class 2 - Low Solubility, High fraction absorbed Class 3 - High Solubility, Low fraction absorbed Class 4 - Low Solubility, Low fraction absorbed Active transport or paracellular transport Sulfasalazine Fa < 20% Marketed drugs. All compounds >20% fraction absorbed except one It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification number of pH conditions for a solubility determination can be bas ed on the ionization characteristics of the test drug substance. For example, when the pKa of a drug is in the range of 3-5, solubility should be determined at pH = pKa, pH = pKa + 1, pH = pKa - 1, and at pH = 1 and 7.5 Table 6. Drug-like properties of the antiplatelets investigated. - A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs
Small changes in milk pH markedly change the total drug concentration of drug having small pKa (e.g., salisylic acid, pKa-3.0). However, relatively large changes in pH does not change the concentration of organic acids with high pka values (sulphanilamide, pKa-10.4) Drug solubility: importance and enhancement techniques. ISRN pharmaceutics, 2012. 2 Yellela SRK. Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. Journal of Bioequivalence & Bioavailability. 2010;2(2):28-36. dosage forms lies within their poor bioavailability. The cause of low oral bioavailability is th
pKa Lipid Solubility Or Hydrophobicity Or Lipophilicity Protein Binding Vasodilation Onset of Action Local Anesthetics are weak bases. Exist in ionized (charged) and unionized forms (uncharged). The percentage of ionized vs. unionized form is dependent upon pKa. When the pKa of a drug = pH, the LA is 50% ionized: 50% unionize 1. Understand the physicochemical properties of drug molecule Physicochemical properties of a drug molecule play an important role in method development. For Method development one has to study the physical properties like solubility, polarity, pKa and pH of the drug molecule. Polarity is a physical property of a compound. It helps an analyst The solubility of many compounds depends strongly on the pH of the solution. For example, the anion in many sparingly soluble salts is the conjugate base of a weak acid that may become protonated in solution. In addition, the solubility of simple binary compounds such as oxides and sulfides, both strong bases, is often dependent on pH
less than that of the unionized drug. The pKa range for acidic drug whose ionization is pH sensitive is around 3.0-7.5 and pKa range for • Aqueous Solubility Most of the drugs are weak acids or weak bases Drugs with low water solubility will be difficult to incorporate into sustained releas Basic pKa accuracy assessment on CHEMBL3301362 assay data. 48% of the measured values were predicted within 0.5 pKa unit, and 73% was within 1 pKa. The report that has been uploaded to the documentation page and is also available here. We were also interested in how accurate our solubility predictor is, thus we picked a dataset that was.
Based on the clinical summary of oral anticancer drugs reported by Willemsen et al., 10 crizotinib, dabrafenib mesylate, erlotinib HCl, gefitinib, imatinib mesylate, pazopanib HCl, and trametinib were selected as model drugs due to their poor aqueous solubility (BCS II or IV) based on the US Food and Drug Administration's (FDA's) reviews. Drug Absorption is Influenced by Ionization state of the drug (pKa) pH of the fluids at the absorption site Lipid solubility (LIPOPHILICITY) Cell membrane Preparatory Work Identify any ionizable functional groups in atorvastatin and indicate a salt form which will have greater aqueous solubility than the drug itsel
Working document QAS/17.699/Rev.2 July 2018 Draft document for comments 70 PROTOCOL TO CONDUCT EQUILIBRIUM SOLUBILITY EXPERIMENTS FOR 71 THE PURPOSE OF BIOPHARMACEUTICS CLASSICIATION SYSTEM-BASED 72 CLASSIFICATION OF ACTIVE PHARMACEUTICAL INGREDIENTS FOR 73 BIOWAIVER 74 1.75 OBJECTIVE OF THE DOCUMENT 76 The objective of this document is to provide guidance on the design and conduct of equilibriu Table: Solubility based classificati n of drug 1. Solution phase equilibrium with solid phase at a stated temperature and pressure . 2. pKa is the dissociation constant of a drug The un-ionized drug is lipid soluble thus permeates through lipid membrane What is a basic drug? To what do the terms cocaine base, crack, freebase and rock refer to? List three different general extraction schemes used to separate different classes of drugs. List three different literature resources when trying to determine solubility of different chemical species. What is pKa? How does it. To achieve that drugs have to be soluble both in water and in lipids. This requirement makes lipophilicity and solubility the two major properties responsible for absorption and bioavailability of drugs. The 1-octanol-water partition coefficient, logP, is well known as one of the major parameters to estimate lipophilicity (or solubility in lipids The amine functionality is the most common functional group found in drug molecules. The primary physicochemical property of importance in the drug chemistry of the amino group is its basicity. Because most amines are basic, salts forms can be generated to facilitate water solubility or solubility in other vehicles for drug administration
vi) pKa of the diffusing substance and the pH of the environment. Let's look at aspirin. Aspirin is a weak acid with a pka of 3. Recall that pka refers to the pH at which a substance is 50% ionized and is also the pH at which a substance will act optimally as a buffer. The chemical formula for aspirin is C9H8O4 2.7 Definition of Lipophilicity and pK a. Lipophilicity is the affinity of a molecule for a lipophilic (non-polar) environment. The pK a of a singly-ionizing compound is the pH at which the molecule is 50% protonated and it provides an indicator of the extent of ionization potential of the compound. Most drugs are either weak acids or weak bases According to FDA guideline, the solubility test should be evaluated based on the ionization characteristics of the tested substance in pH = pKa, pH = pKa + 1, and pH = pKa−1 . The pKa value of NF has been reported as 8.2 [ 6 , 19 ], which is above the human gastrointestinal tract (GIT) physiological range - A drug in its ionic form is more readily soluble in Polar solvents compared to its un-ionized form. - The extent of drug ionization of a weak base or acid is dependent on the pH of solution and the pKa of the drug --> thus, so will aqueous solubility Solubility is Affected by pH. The pH of an aqueous solution can affect the solubility of the solute. By changing the pH of the solution, you can change the charge state of the solute. If the pH of the solution is such that a particular molecule carries no net electric charge, the solute often has minimal solubility and precipitates out of the.