pharmaceutics study guide exam 1

pharmaceutics

the pharmacy discipline concerned with the scientific and technological aspects of the design and manufacture of dosage forms 

importance of pharmaceutics in pharmaceutical science

·       Pharmaceutics convert drugs into medicine 

·       One of the most diverse subject areas in pharmaceutical science 

pharmaceutical formualtion

- the process of designing and producing a medication in a specific form. Involves combining the active drug with excipients to create a final product that is safe, effective, and stable 

• involves various pre-formulation studies to select appropriate excipients, determine the optimal dosage from, and conduct stability tests  

pharmaceutical formulation differs from compounding

·       in that it is large scale and produced by pharmaceutical companies to be standardized and mass produced, regulated by the FDA 

·       Compounding is customized for every patients, small scale, and not FDA approved but must comply with state and federal regulations 

stages of drug development

• New chemical entity 

• Preclinical studies 

• investigational new drug application (IND)- FDA review 

• Preclinical studies 

• Clinical trials 

•   New drug application- FDA action 

importance of pharmaceutics in the new drug development process

• Identifying potential drug candidates and with desirable properties, such as solubility and stability, which are crucial for further development 

• Formulating drugs for laboratory and animal testing. This ensures that the drugs are in a suitable form for testing their safety and efficacy 

• In clinical trials, pharmaceutics ensures that the drug formulations are consistent and accurate, which is essential for reliable testing on human subjects 

united states pharmacopeia (USP)

• set public standards for medicines, food ingredients, and dietary supplements 

• continuously revised and updated

• organized sets of monographs or reference books of standards that is used by those involved in the production of drugs and pharmaceutical products

  • ensure quality and safety of medication

national formulary (NF)

• focuses on providing standards for excipients, botanicals, and other ingredients used in drug formulations 

• continuously revised and updated

• organized sets of monographs or reference books of standards that is used by those involved in the production of drugs and pharmaceutical products

  • ensure quality and safety of medication

monograph

• written document that reflects the quality attributes of dosage forms and pharmaceutical material approved by the FDA 

• The standards set forth are specific to the individual therapeutic agent, and pharmaceutical material to ensure purity, potency, and quality 

• Includes structure, chemical formula, identification, assay protocol, analysis, impurities, procedure, solubility requirements, acceptance criteria, specific tests, additional requirements 

chapter 795

nonsterile compounding, guidelines for nonsterile preparations (creams, ointments, oral suspensions) 

chapter 797

sterile compounding, procedures and requirements for sterile preparations (injections and eye drops) 

reasons for incorporation of drugs into various dosage forms

• Accurate dosing 

•   Protection of the drug 

• Improved patient compliance 

• Controlled release 

principles of dosage form design

1.     Biopharmaceutical considerations 

2.     Drug factors 

3.     Therapeutic considerations 

importance of pre- formulation studies in dosage form design

• is a consideration of the steps that need to be performed before the formulation itself can begin 

• Involves a full understanding of the physiochemical properties of drugs and other ingredients in a dosage form and how they may interact 

• Results of tests carried out at this stage of development can give a much clearer indication of the possible dosage forms for a new drug candidate

route of administration

• the way through which the dosage from is administered into the body 

• Dosage forms can be administered by various delivery routes to maximize therapeutic response 

•   Can be  

  1.    Site specific delivery 

  2.   Systemic delivery 

principal objective of dosage form design

 achieve a predictable therapeutic response to a drug included in a formulation that can be manufactured on a large scale with reproducible product quality 

properties to consider when designing a dosage form

• Water solubility 

• Log P 

• Molecular weight

• Stability in solution 

•   Enzymatic degradation 

5 qualities of an ideal dosage form

1.     One dose in a manageable size unit 

2.     Palatable or comfortable 

3.     Stable 

4.     Convenient/easy to use 

5.     Release of drug 

excipients

·       (inactive ingredient/pharmaceutical ingredient)- any component other than the active substance present in a medicinal product or used in the manufacture of the product; usually well-defined functions in a drug product; considered inactive from a therapeutic or pharmaceutical response perspective 

·       Can be colorings, flavors, sweeteners, binders, fillers, etc. 

Handbook of pharmaceutical excipients

• Presents monographs on >400 excipients used in dosage form preparation 

• Each monograph includes information about chemical names, molecular weight, chemical and physical properties, incompatibilities and interactions with other excipients and drug substances, safety, stability, and handing information, and application in pharmaceutical formulation or technology 

properties of excipients

• Pharmacologically inert 

• Minimal toxicity 

• Cost effective 

• Stable and reproducible 

• Don't interfere with the therapeutic efficacy of API 

functions of excipients to ensure the quality, safety, and efficacy of administered dosage forms

•     Dosage form 

• Modified release and absorption 

• Stability

safety issues of excipients

• Drug-excipient interactions- possible as many popular excipients, such as alcohol and organic acids have functional chemical groups 

• Effect of reactions between the API and the excipients that could lead to adverse effects: 

  1.   Reduction in drug concentration 

  2.    Unknown structure and biological activity 

flavoring

• May be derived from natural components (fruit) or prepared artificially 

• May either be water or oil-soluble 

• In liquid pharmaceutical products are added to the solvent or vehicle component of the formulation in which it is most soluble or miscible 

• Artificial flavors are used in liquid preparation at levels of 0.1%-0.2% whereas natural flavors are used within the 1-2% range 

•   Flavors can degrade due to exposure to light, temperature, headspace oxygen, water, enzymes, containments, and other product components 

• Must be carefully selected and checked for stability  

sweetening

•   Sucrose is the main naturally occuring sweetener used in pharmaceutical preparations 

• Ex of artificial sweetening agents are aspartame, saccharin, and cyclamate 

• Artificial sweeteners have faced challenges over their safety by the FDA and restrictions to their use 

• Artificial sweeteners approved by FDA 

  1. Acesulfame potassium 

  2. Aspartame 

  3.   Sucralose 

  4.   Saccharin 

• Artificial sweeteners are better for diabetic patients 

coloring

• Most coloring agents used in pharmaceutical preparations are synthetic 

•    Can be either lake pigments or dyes 

•    About 90% of the dyes used in products FDA regulates are synthesized from a single colorless derivative of benzene called aniline 

  • Aniline dyes 

  •   FD&C dyes 

  •    Lake pigment 

aniline dyes

• essentially pure colorants that provide very deep, vibrant colors, are water soluble, making them easy to incorporate into various products 

  • Preferred in applications where vibrant colors are desired 

FD&C dyes

(federal food, drug, and cosmetic act dyes)- coloring agents (aniline dyes) that are approved by the FDA 

lake pigments

• made by precipitating a dye with an inert binder (metallic salt). Composed of a dye, aluminum hydroxide, and water. Thet are water insoluble (oil-soluble) 

• Preferred for products requiring stable, nonbleeding coloration such as pharmaceutical coatings 

percent of artificial flavor in liquids

0.1-0.2%

percent of natural flavor in liquids

1-2%

percent of colorant in liquids

0.0005-0.001%

percent of colorant in solid forms

0.1%

four key processes involved in pharmokinetics

• absorption

• distribution

• metabolism

• excretion

pharmokinetics

the study of how a drug moves through the body, encompassing 4 key processes 

absorption

process of drug entering the blood circulation

distribution

process of drug transfer to target the tissue

metabolism

process in which the drug is transformed into other substances, called metabolites (liver)

excretion

the process in which a drug is removed from the body (kidney)

intermolecular forces

·       Molecules (including drugs) can exist as gases, liquids, or solids because there are __ that help hold them together and push the apart 

cohesion

the attraction of like molecules

adhesion

the attraction of unlike molecules

repulsion

a reaction between 2 molecules that forces them apart

intramolecular bonding

forces that keep a molecule together (colvalent, polar) 

• within the molecule itself

intermolecular forces

• forces between molecules that keep a certain state of matter (dipole-dipole) 

  • Determine some properties such as the meltign points of solids and the boiling points of liquids 

  •   Largely governed by electron orbital reactions 

  • Nonpolar covalent bond- bonding electrons shared equally between 2 atoms. No charges on atoms 

  • Polar covalent bond- bonding electrons shared unequally between 2 atoms. Partial charges on atoms 

  • Intermolecular forces are weak compared to intramolecular forces 

dipole

• polar molecular that has 2 poles 

• will form as a result of unequal sharing of electrons between atoms in a covalent bond resulting in one atom being relatively negative and another that is relatively positive 

•   Unequal sharing of the electrons is the result of the difference in electronegativity between atoms 

•   A polar covalent bond creates a dipole within a molecule 

types of intermolecular forces

• Dipole-dipole interaction 

•   Induced dipole  interations (dipole-induced dipole and ion-induced dipole) 

• Ion-dipole interaction 

• Hydrogen bond- interaction between a molecule with a hydrogen atom and a strongly electronegative atom (O,N,F) 

• all are van der waals forces

other attractive forces (inter or intramolecular)

•    Ionic (ion-ion) interactions 

• Hydrophobic interactions- created in proteins by the preference or hydrophobic areas of the molecule to be sequester away form polar water molecules 

repulsive forces

• When the electron clouds of 2 atoms become clsoe enough to enter the same space and repel each other 

• At a distance of 0.3-0.4 nm, the attractive forces will equal the repulsive forces and the volume occupied by the 2 atoms is most stable 

gaseous state

rapid movement and collisions of molecules with each other and the walls of the container; hence, they exert a "pressure". Another characteristic is that they occupy a volume 

liquid state

liquids are in between gases and solids; they contain more energy than when solid but less energy than when in the gaseous state 

solid state

solids are arranged in fixed geometric lattices or patterns. Crystalline or amorphous  

challenges of liquid drug formulation

• Many liquids are volatiles; this may lead to evaporation loss (must be physically sealed from atmosphere) 

•   Liquid drugs intended for oral administration cannot always be formulated into tablet form (solid), without chemical modification 

crystalline solids

• Crystal 

•    Orderly arrangement of constituents (units) that permits optimal attractive interactions between adjacent molecules within the solid 

• The orderly-arranged constituents can be molecules, atoms, or ions 

•   Exhibit definite shapes 

• Crystalline habit- a term used to describe the shape of the drug crystal that can be determined by visual inspection (microscope) 

•   A drug's crystal habit may be described as needle-like (acicular), pyramidal, prismatic, and tabular 

• The shape of the drug particle is important to some properties related to the formulation of dosage forms such as flowability, dispersibility, and aerodynamic properties 

•   Dispersibility- the availability of a powder to disperse quickly and evenly into water without forming lumps 

• Aerodynamic properties of particles (inhaled drugs)- how they move in the air and how they settle down 

amorphous solid

•   The molecules are arranged in a random manner that is similar to the liquid state, but thet are solid 

•   The specific conditions used for the precipitation or recrystallization of a substance following the drug synthesis process determine the type of a solid formed (crystalline or amorphous) 

• These methods used to prepare amorphous solids do not allow the drug molecules sufficient time to form orderly arrays, and consequently, they solidify in a disorderly state

•   Whether a solid drug is amorphous or crystalline has been demonstrated to affect other physiochemical properties 

• For example, whether to use an amorphous or crystalline solid to prepare a solution, there may be a difference in the rate of dissolution (how fast the solid will dissolve in a solvent), but once dissolved, the molecules are the same and act identically 

melting point

• The temperature at which a pure solid convert into the liquid state is called the melting point 

• is a measure of the strength of intermolecular interactions (attractive forces) between molecules in a solid 

•   The lower the melting point a solid has, the less energy is required to disrupt interactions within the solid to become a liquid 

• The higher the melting point a solid has, the more energy is required to disrupt interactions within the solid 

heat of fusion

the amount of heat required to convert a solid into liquid at its melting point when the pressure of the environment is kept constant 

how heat of fusion and melting point are important in purity determination

• A pure substance is ordinarily characterized by a very sharp melting peak 

• An altered peak or a peak at a different temperature may indicate an adultered or impure drug 

• The larger the value of heat of fusion and melting point, the stronger the intermolecular binding forces in the soid 

• For pharmaceutical solids, the heat of fusion and melting point can be determined using techniques like differential scanning calorimetry (DSC) 

polymorphism

the phenomenon whereby molecules arrange themselves in more than one pattern within a crystal resulting in different polymorphic forms 

most stable polymorph

• one polymorph in which the intermolecular attractive forces are best aligned 

• highest melting point and least soluble

metastable form polymorph

• which represents a higher energy state 

• less stable but has better solubility and bioavailability 

• can spontaneously convert to the more stable form over time (due to high energy) 

solvates

orderly arrangements of drug molecules that include solvent molecules in the crystalline lattice 

hydrates

•   If the crystallization solvent is water

• It has been estimated that about 30% of drugs form these

• may lose their waters of crystallization and become sticky; a process called efflorescence 

• The solvent or water molecule in the solvate is incorporated in an exact molar ratio such that the number of waters per drug molecule will be included in the name of the solid 

• Ex: magnesium sulfate heptahydrate and amoxicillin trihydrate 

cocrystals

•   crystals composed of an active drug species and another organic molecule 

• The other molecule in the crystal is called a coformer, it forms hydrogen bonds with the drug molecule 

• formulation is one approach to the modification of the physical properties of solid drugs

range of particle size

from 0.1 micrometers- 1000 micrometers in diameter 

advantages of particle size reduction during formulation process

• Increases surface area, which increases dissolution rate and bioavailability 

• improves mixing or blending of several solid ingredients if they are reduced to approximately the same size 

solution

a homogenous mixture of the molecules of one substance with another 

solubiltiy

the extent to which the solute dissolves 

saturated solution

when an excess of a solid brought into contact with a a liquid, molecules of the solid are removed from its surface until equilibrium is established between the molecules leaving the solid and those returning to it, at the temperature of the experiment 

supersaturated solution

• when an excess of solid is brought into contact with a liquid

• reaches past the value of saturated solution

• usually accomplished through the addition of heat

reasons for API to have sufficient water solubility

• Up to 40% of drug candidates have been abandoned because of poor aqueous solubility 

• Many dosage forms are solutions of drug in water- oral and parenteral solutions or solutions for the eye, ear, and nose 

• Dosage forms that are not solutions must dissolve in aqueous body fluids before they can move across membrane barriers in the body (ADME) 

solubility greater than 10 mg/mL

optimal for oral delivery

solubility less than 1 mg/mL

may be problematic and salt formation may be used to improve solubility

Noyes-Whitney dissolution model

•   Rate of solution = DA/I (C1-C2)

• A solid particle dispersed in a solvent is surrounded by a thin layer of solvent having a finite thickness

• The layer is an integral part of the solid and is referred to as the stagnant layer

•    D is a proportionality constant called the diffusion coefficient (cm2/s)

• C1- concentration of the solute in the stagnant layer at the surface of the solid

• C2- concentration of the solute on the farthest side of the stagnant layer

•    A- surface area of the solid (cm2)

•    Also called the diffusion layer method for dissolution

• Regardless of how fast the bulk solution is stirred, the stagnant layer remains part of the surface of the solid, moving wherever the particle moves

• Dissolution rate of solid= the rate at which a dissolved solute particle diffuses through the stagnant layer to the bulk solution

• The driving force behind the movement of the solute molecule through the stagnant layer is the difference in concentration (C1-C2)

• The greater the difference in concentration the faster the diffusion rate (frick’s first law) and faster the dissolution rate, assuming the (I) stays constant

• The dissolution rate is also directly to the surface area of the solid

• The dissolution rate is inversely proportional to the length of the path through which the dissolved solute molecule most diffuse

factors that affect the dissolution rate of solid particles

• Physical form- non crystalline (amorphous) solids are generally more soluble solids. Also, different polymorphic forms, and solvates will have different solubilities

• Temperature

  • Increasing temperature generally increases solubility. Most solutes absorb heat upon dissolution due to the necessity of breaking the strong solute-solute interactions (NH4Cl, NH4NO3, NaCl)- endothermic reaction

  •   A few solutes due to very weak solute-solute interactions; they give off heat during dissolution increasing the temperature will decrease the solubility because the system will try to counteract the added that by favoring the formation of the solid phase. (NaOH,CaCl2)- exothermic reaction

• pH

  • pH of the aqueous medium affects the ionization of acid/base drugs. As ionization increases, solubility will increase

• heat of solution the amount of heat absorbed or released when a solute dissolves in a solvent

  •     dH is negative if energy (heat) is released (exothermic)

  • dH is positive if energy (heat) is absorbed (endothermic)

• formulation components, particle size, solubility of the API, pH of the medium, agitation/stirring

relationship between particle size and dissolution rate

• Surface area of fixed mass of particles s inversely proportional to the particle size

• The greater the surface area the greater the molecules are in contact with solvent, the faster the dissolution

• Small particles go into solution faster than large particles (smaller size, increase A, A is directly proportional to rate)

lowry-bronsted acid

-       a substance that can ionize in solution to give a hydrogen ion (proton)

•   A molecule that is capable of donating a proton (H+)

lowry bronsted base

-       a substance that can ionize in solution to accept a proton

•   A molecule that is capable of accepting a proton (H+)

ionization of strong acids vs weak acids

• In aqueous solutions of acidic and basic drugs, equilibria exist between undissociated (unionized) molecules and their ions (ionized molecules)

• In a solution of a weakly acidic drug HA, the equilibrium may be represented by

  • HA – H2O <->  A- + H3O+

• HA= acid, ionized

• A-= base, unionized

•     In a strong acid- all are dissociated

• In weak acid, there is a degree of ionziation

chemical parameters that determine extent of ionization

• Chemical structure of the drug, and therefore the pKa value(s) of any functional groups with acid- base character (can’t change)

•   pH of the aqueous medium in which the drug is found (can change by adding acid/base)

acidic drug ionization

§  HA – H2O <->  A- + H3O+

basic drug ionization

§  B.. + H20 <-> B..H+OH-

uncharged or cationic

we most commonly encounter acids with a charge of __

uncharged or anionc

bases will be either ___ or ___

conjugate acid-base pair concept

• A -> <- H+ + B

• The ionization process will always involve both species (acid + base) and they are known as conjugate acid-base pairs

• The acid-base pari of substances is related through their mutual ability to gain or lose a proton

• An acid will not release a proton unless a base capable of accepting it is present simultaneously

• Acid CH3COOH– Base CH3COO-

• HA + H2O <-> H3O+ + A-

• HA= acid

•    H2O= base

• A-= conjugate base (the drug anion)

• H3O+= conjugate acid

• B + H2O <-> BH+ + OH-

• B= base

• H2O= acid

• OH-= conjugate base (drug anion)

•   BH+= conjugate acid

degree of ionization using Henderson-Hasselbalch equation

- The degree of ionization of a drug in a solution can be calculated from rearranged Henderson-Hasselbach equations for weak acids and weak bases (if the pKa of the drug and the pH of the solution are known

- Henderson Hasselbach equation

pH = pKa – log [base]/[acid]

- to calculate the degree of ionization for an acidic drug

pH = pKa + log [A-] / [HA]

pH – pKa = log I/U

- to calculate the degree of ionization for a basic drug

pH = pKa + log [B] / [BH+]

pH – pKa = log U/ I

acid ionization curve

have the same shape as sulfamethohoxazole. What will change is where the curve lies on the graph. This will be dictated by the pKa of the acid because that always tells you where the 50% ionized point

- Sigmoidal shape, starts low and goes high

base ionization curves

will have the same shape as chlorpheniramine. What will change is where the curve lies on the graph. This will be dictated by the pKa of the acid conjugate because that always tells you where the 50% ionized point is

- Sigmoidal shape, starts high, goes low

importance of the degree of ionization for ADME and formulation of drugs

- Help in choosing vehicles for drugs that will enhance their solubility since the ionized form will be more water soluble (formulation process)

- The ionized form is considered the excretable form. It promotes drug excretion, as it more soluble in urinary water

- The unionized form is considered the absorbable form. It is highly lipophilic and this increases transport across biological membranes and promotes absorption into the blood circulation from sites of administration

ionization of amphoteric drugs

can function as either weak acids or weak bases in an aqueous solution and have more than one pKa value

• The acidic pKa refers to the pKa of the acidic functional group

• The basic pKa refers to the pKa oof the basic functional group

salt formation

a central pre-formulation process as it is associated with significant advantages over the parent drug

• The process of salt formation is relatively simple and involves pairing the parent drug molecule with an appropriate counterion (salt former or salt forming agent)

• The drug should contain ionizable functional groups that allow sufficient ionic interaction between the drug and the salt former

• A salt is formed by an acid-base reaction involving a proton donation and acceptance

• The resulting salt is a neutral complex (net charge = 0)

salt formation for acidic drugs

• To form their conjugate base (their salt forms), they must be induced to donate a proton by reaction with strong base

• The strong bases used to form basic salts from acidic drugs are the hydroxides of the alkali and alkaline earth metals [NaOH, KOH, Ca(OH)2, and Al(OH)3]

• Note the equilibrium established between conjugate acid-base pair forms and the balance of charge in the equations

• ionized, water soluble

• anionic, basic

• forms basic salt

salt formation of basic drugs

• Amines accept proton from both inorganic and organic “feeder acids” to from their ionized acid conjugates (acid salts)

• The inorganic salts used to make acid salts include HCl, H2SO4, H3PO4, and NHO3

• organic salts commonly used to make acid slats include maleic, fumaric, tartaric, succinic, and citric acids

• When the unionized amine accepts H+ It becomes cationic (remember bases have cationic conjugate acids)

• This positive charge is balanced by the negatively charged counterion of the feeder acid that remains after the proton transfer

• ionzied, water soluble

• cationic and acidic

• acidic salt

name basic salts

, you simply couple the name of the metal ion that came from the strong base with the name of the original acid (calcium fenoprofen). All drugs named this way will be ionized, water soluble, and basic in this form. The metal is your big clue in identifying basic salts…. Look for it!!

• Sodium sulfisoxazole (made from sulfisoxazole free acid and NaOH)

• Potassium PenV (made from penicillin V free acid and KOH)

• Aluminum aspirin (made from aspirin free acid and Al(OH)3)

name acidic salts

, combine the name of the original base with the name/modified name of the “feeder acid” used to make the salt. The modified name is the name of the anionic counterion.. in other words, the piece of the original “feeder acid” that is left after it donates its proton to the molecular base

• Ex of marketed acidic salts

• Morphine sulfate (made form morphine free base and sulfuric acid)

• Triplennamine citrate (made from triplennamine free base and citric acid)

• Physostigmine maleate (made from physostigmine free base and maleic acid)

advantages of slat formation for drugs

• Improves water solubility (important for formulating a drug as a specific dosage form, solutions for example

• Accelerates dissolution rate (important for solid dosage forms)

different salt forms of the same API can exhibit varying properties

• Many drugs are now produced in more than one salt form

• When multiple drug salts of the same agent exist, they are marketed as therapeutically equivalent and clinicians often treat the different salt forms identically (in some cases different salts will be different)

• Diclofenac potassium is absorbed into the body more quickly than the sodium salt, which is useful where immediate pain relief is required

buffer

• the change in pH can be mitigated using this

• compounds or mixtures of compounds that, by their presence in solution, resist changes in pH upon the addition of small quantities of acid or alkali

buffered solutions

• solution that contains a buffer

• when partially neutralized weak acids or bases are present in aqueous solution, the addition of small amount of strong acid or strong base causes or no detectable change in pH

acidic buffer

• Mix a weak acid and its conjugate base salt (acetic acid/sodium acetate)

• Excess OH- are neutralized by acetic acid, since added OH- are not available, pH does not change

• Excess H+ are neutralized by acetate (conjugate base) since added H+ are not available, pH does not change

• Other ex of acidc buffer systems

  • H2CO3/NaHCO3 (carbonic acid/ sodium carbonate)

  • H3PO4/NaH2PO4 (phosphoric acid/ sodium phosphate)

  • HCOOH/HCOONa (formic acid/sodium formate)

• pH < 7, a weak acid + its salt with a strong base