Lecture 11 - Salt Forms and Solution Formulation Fall 2024 PDF

Foundations of Pharmaceutical Sciences Lecture #11 I. Salt forms II. Solution formulations Dr. Lewis Stevens [email protected] 1  Overview Discuss salt forms and their classification as acidic/basic Calculation of pH...

Foundations of Pharmaceutical Sciences Lecture #11 I. Salt forms II. Solution formulations Dr. Lewis Stevens [email protected] 1  Overview Discuss salt forms and their classification as acidic/basic Calculation of pH and fraction ionized for salt forms One of key issues that ionic equilibria helps us understand is drug stability Physical vs. chemical stability Describe the excipients of solution formulations and their role, Buffers, preservative, tonicity, antioxidants, solvents 2  Solution formulation Review questions. When assessing the strength of two weak acids, a) the acid with a higher pKA is stronger b) the acid with a lower pKA is stronger When assessing the strength of two weak bases, a) the base with higher pKA is stronger b) the base with lower pKA is stronger 3  Solution formulation Review questions. When assessing the strength of two weak acids, a) the acid with a higher pKA is stronger b) the acid with a lower pKA is stronger When assessing the strength of two weak bases, a) the base with higher pKA is stronger b) the base with lower pKA is stronger 4  Solution formulation pKA = 9 Our previous examples, where we calculated fraction ionized, had only one ionizable functional group. For molecules with more than one ionizable group, we look at each group and determine % ionized for each one. pKA = 4 Generally, except for very large molecules, if at least one functional If a solution of this drug was buffered group is ionized, at a given pH, there to pH = 7, the net overall charge on won’t be a concern of precipitation this molecule is zero. Is this molecule unionized at pH = 7? ANS: Net overall charge is zero. At pH = 7, the aliphatic is 100% ionized (has a + charge) and at pH = 7, the carboxylic acid is 100% ionized (has a – charge). 5  Solution formulation Cl- A very common pharmaceutical form you’ll often encounter is the salt form, Lidocaine HCl Naproxen Sodium Ephedrine Sulfate (lidocaine HCl) Salt forms of a drug compound are often used to significantly boost their water solubility Salts are formed from the reaction of an acid and a base (naproxen sodium) Here we’ll look at acid-base reactions by which typical salts are formed 6  Solution formulation There are a variety of ways salt forms may be indicated on the drug product insert. Consider atorvastatin calcium. In this example, the ionized group is shown. A carboxylate carries a -1 charge, and since the counterion (Ca) has a +2, then there are 2 ionized atorvastatin molecules for every Ca2+. This indicates the solid form is a hydrate with 3 water molecules for every 2:1 atorvastatin Ca salt 7  Solution formulation There are a variety of ways salt forms may be indicated on the drug product insert. Another way to represent a salt is shown for acebutolol HCl. This does not mean that acebutolol and HCl are distinct species, but rather the HCl salt. What would the actual species look like? 8  Solution formulation There are a variety of ways salt forms This is the may be indicated on the drug product insert. Another way to represent a salt is shown for acebutolol HCl. - + This is the only ionizable group in acebutolol. 9  Solution formulation Salts of acidic drugs can be made by reaction with a strong base, typically sodium or potassium hydroxide weakly associated counterion + KOH → H2O + Penicillin V Potassium Penicillin V Penicillin V parent molecule is an The salt form looks like the conjugate acid (due to carboxylic acid group) base of the weak acid free form. So, if you put this salt form into water, Salt compound name includes the counter ion, e.g. would you expect the pH greater or sodium or potassium, either before or after the compound name. lower than 7? 10 Solution formulation weakly associated counterion + KOH → H2O + Penicillin V Potassium Penicillin V Penicillin V parent molecule is an The salt form looks like the conjugate acid (due to carboxylic acid group) base of the weak acid free form. So, if you put this salt form into water, would you expect the pH greater or lower than 7? ANS: The pH would be above 7. If you put potassium penicillin V (the conjugate base of Penicillin V) into water, it will act like any other base. You would use a base pH equation to calculate pH of the solution. 11  Solution formulation Another example. Starting material is a weak acid (see the imide group) that is converted weakly associated to a salt form by a strong base (NaOH) counterion Na+ - + NaOH → H2O + Phenytoin Phenytoin Sodium Parent molecule is an acid Salt is a base. Note again, (due to imide group) conjugate base of the weak acid free form. 12  Solution formulation Consider a 0.1 M solution of sodium phenytoin, what’s the pH going to be? (pKA = 8.3) Na+ - a) 12.40 b) 10.65 c) 3.55 d) 1.00 13  Solution formulation Consider a 0.1 M solution of sodium phenytoin, what’s the pH going to be? (pKA = 8.3) When we put the salt form of a drug in solution, the first thing that happens is the salt dissociates. Then we have a base in solution (specifically the conjugate base of phenytoin) - + H 2O ↔ OH − + Is the pH of the solution going to above or below 7? What equation are you going to pick, weak acid or weak base? 14  Solution formulation Sodium phenytoin is going to act like a base, and therefore we select the base pH equation. Expect a solution of sodium phenytoin to be higher than 7. I selected this version of the base pH equation, but you choose any and you’ll get the same answer. [OH − ] = K B Cb Since pKA = 8.3, then pKB = 5.7 and then, K B = 10 −5.7 And, [OH − ] = K B Cb = 10 −5.7 ⋅ 0.1 = 4.47 × 10 −4 pOH = − log[OH − ] = − log[4.47 × 10 −4 ] = 3.35 and pH = 14 − 3.35 = 10.65 15  Solution formulation For the previous example, you could use any equations for a weak base, and you would arrive at the same answer. weak base 16  Solution formulation Consider a 0.1 M solution of sodium phenytoin, what’s the pH going to be? (pKA = 8.3) When we put the salt form of a drug in solution, the first thing that happens is the salt dissociates. Then we have a base in solution (specifically the conjugate base of phenytoin) - + H 2O ↔ OH − + 1 1 Another way to 𝑝𝑝𝑝𝑝 = 14 + 𝑝𝑝𝐾𝐾𝐴𝐴 + 𝑙𝑙𝑙𝑙𝑙𝑙 𝐶𝐶𝑏𝑏 = 14 + 8.3 + 𝑙𝑙𝑙𝑙𝑙𝑙𝑙.1 = 10.65 2 2 the same answer 17  Solution formulation Salts of basic drugs can be made by reaction with a strong acid, typically hydrochloric, sulfuric, nitric or perchloric acid. Cl- H+ + HCl → Procaine Procaine hydrochloride or procaine HCl Parent molecule is a base. Recognize the salt is the conjugate acid The pKA for procaine is 8.9. of parent base When you put procaine HCl in solution is the pH going to be above or below 7.0? ANS: The pH would be below 7. If you put procaine HCl (the conjugate acid of procaine) into water, it will act like any other acid. You would use a acid pH equation to calculate pH of the solution. 18  Solution formulation Question. What would the pH of a 0.1 M solution of procaine HCl be? a) 6.95 b) 4.95 c) 2.95 d) 1.00 19  Solution formulation Question. What would the pH of a 0.1 M solution of procaine HCl be? First, this species is the conjugate acid of the procaine free base. We recognize that we’re dealing with acid, so we select an acid pH equation. I chose this one [ H 3O + ] = K A C a pKA = 8.9, so K A = 10 −8.9 Now plug in what we know, [ H 3O ] = + K ACa = 10 −8.9 ⋅ 0.1 = 1.12 × 10 −5 And, then pH = − log[ H 3O + ] = − log[1.12 × 10 −5 ] = 4.95 20  Solution formulation Concept question. What would you expect the fraction ionized be for a salt form? a) near zero b) near 100% 21  Solution formulation Now, fraction ionized is calculated with From the previous procaine HCl example, we respect to the free form, i.e. the calculated the pH of the solution to be, pH = unionized functional group. This is what 4.95. guides our selection of the acid or base equations. The pKA for this tertiary amine is given as 8.9. Continuing with the example for Plugging in what we know, procaine HCl, the functional group of interest is the tertiary amine. 8.9−4.95 𝐵𝐵𝐵𝐵 + 10 = 103.95 = 𝐵𝐵 This tertiary amine is a basic functional group. Thus to calculate the fraction ionized select the base fraction ionized 103.95 equations: ( pK A − pH ) [ BH + ] %𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 = × 100 ≈ 100% 1 + 103.95 10 = [ B] [ BH + ] Do your sanity check, i.e. the [ BH + ] [ B] % ionized = + × 100 = × 100 pH is 2 units below the pKA [ B ] + [ BH ] [ BH + ] 1+ for a basic functional group. [ B] 22  Solution formulation As we’ve seen already, many drugs have poor water solubility and some of those drugs lack an ionizable functional group Digoxin, shown to the right To accommodate this for a solution formulation, e.g. injection, co-solvents are needed Alcohol Propylene glycol These inactive ingredients (excipients) are vital Remember, a drug product components to a preparing a safe and effective formulation typically contains more than Stability of the drug product is a primary concern just the drug. Excipients are a While our current emphasis is solution formulations; vital component to ensuring however, this true for all types of dosage forms drug product quality. 23  Solution formulation Our definition of stability is as follows: Absence of unacceptable changes in the performance properties of a pharmaceutical product in the presence of environmental A primary oversight body to stress associated with manufacturing, the pharmaceutical industry to shipping, storage and use. ensure product quality is adequately documented and The two primary classifications of stability verified. are: Physical – non-covalent changes to the product components For physical instability, the molecules remain the same. Chemical – changes to covalent bonding Both mechanisms of instability can be sensitive to changes in pH. of the product components For chemical instability, the molecules are changed, so you’re no longer dealing with the SAME molecule. 24  Solution formulation In a solid form, the molecules have a specific arrangement in space. Physical instability may arise through multiple ways, e.g.: Changes in structure (not at the molecular level but the solid phase level) This is known, as polymorphism. Changes in phase (soluble components → insoluble solids) Non-covalent interactions between drug and excipients/co-solvents Remember, changing the spatial Non-covalent interactions between drug and arrangement of the same molecule packaging components yields a different polymorph, and this Physical instability can manifest as, e.g.: impacts the physical properties of Precipitation* (change in pH may change the solid drug: dissolution, drug solubility leading to precipitation) compaction, kinetics, bioavailability, etc. Aggregation (particularly problematic for biopharmaceuticals) Changes in pH particularly when Complexation administering two drugs through single Phase transformation IV line can lead to incompatibility. 25  Solution formulation Apart from the example of IV compatibility, changes in physical stability can subsequently result in, Dissolution failure – If the drug dissolves at different rate, it’s bioavailability is going to change. (Remember, the ritonavir example) Mechanical failure – tablets lose their integrity, break apart = poor dose consistency Sedimentation – Precipitation (drug comes out of solution) Partitioning – Phase separation (same idea as sedimentation, but generally for liquids) Loss of potency 26  Solution formulation Excipients are introduced into the formulation to improve efficacy and product stability Classes of excipients include, e.g. Solvent and co-solvent, preservatives, antioxidants, buffers Typical pharmaceutical solvents, Water Alcohols These are miscible with water and Alcohol USP, 94.9 – 96.0% v/v of C2H5OH typically used to solubilize poorly Glycols water-soluble compounds. Glycerin There are limits with how high the alcohol % (v/v) can be in an orally Propylene glycol ingested preparation, so need to calculate what minimum quantity would suffice. Oils 27  Solution formulation Buffers are another important excipient in solution formulation. Buffers are designed to maintain the solution at a constant pH (we’ll discuss more about these later) Common pharmaceutical buffers are shown to the right. Acidifying and alkalizing agents are used for pH adjustment (up, alkalizing) and (down, acidifying) 28  Solution formulation pH is important to dosage design to ensure adequate solubility so the formulation remains a stable product for administration. rate of degradation Mixing solutions of significantly different pH and lead to physical instability (precipitation of the drug) Shown to the right is a pH rate profile. Those regions circled designate the best formulation pH with respect to chemical stability. Often the pH of a solution formulation is selected to (1) maintain solubility and (2) minimize potential chemical degradation. Increasing [H+] Degradation is a bigger concern for solutions than for solids, i.e. tablets. Increasing [OH-] 29  Solution formulation Preservatives – added to nonsterile dosage forms to inhibit microbial growth Propylene glycol (in most formulations) effective at 10% w/v At solution pH less than pH = 3 or greater than pH = 9, then preservatives aren’t generally needed 30  Solution formulation Oxidation is another primary degradation mechanism, generally follows an auto-oxidation process. Initiation In: Initiator (could be drug, Propagation excipient or trace metal) Termination An initiating event (not O2 acting directly on the drug) generates a drug radical (H-abstraction) (unpaired electron) that is very reactive. drug Metal ion, light, heat Radical species propagate the reaction further generating more radical species. Termination step occurs when two radical species join to together to form a non-radical chemical bond. 31  Solution formulation Chelating agents and antioxidants are included to help reduce potential of oxidative degradation. Chelating agent – complexes with ions metal ions, e.g. Edetate calcium disodium Edetate disodium EDTA – ethylenediaminetetraacetic acid Antioxidants – easily oxidized, e.g. sulfite family, act as scavengers to protect the drug from oxidation Reducing agent, e.g. Na thiosulfate, act to reduce an oxidized species 32  Summary Salt forms of drugs are routinely used to Na+ boost water solubility We can treat these forms in a similar way as seen in Lecture 1. It’s important to recognize the drug product is more than just the drug Solvent system Preservatives Buffers Antioxidants All deliberately chosen to ensure an effective and safe drug product Combining drug products without paying attention to solvent system, buffer, or excipients has the potential for physical and chemical instabilities 33