Foundations of Pharmaceutical Sciences Exam 4

Examples of preparations which are solutions

• syrup

• mouthwash

• gargle

• nasal spray

• nasal douche

• inhalation

• infusion

• injection

• enema

• eye drop

What defines a solution?

• homogeneous

• contains two or more components

• one-phase system (no visible separation of components)

• types of solutions: aqueous or non-aqueous

• liquid preparation in which all the ingredients are completely dissolved, formina a clear and uniform mixture

Challenges in formulation solution dosage forms

ensuring the drug fully dissolves and remains in solution throughout its shelf life, while still being safe, palatable, and effective

• equal distribution in each dose

• if a drug doesn’t dissolve, it won’t work

Strategies to increase drug solubility

• cosolvent system

• pH control

• solubilization

• complexation

• chemical modfication

• particle size control

What happens when we mix 2 liquids?

the resulting intermolecular interactions involve

• solvent 1 and solvent 1

• solvent 1 and solvent 2

• solvent 2 and solvent 2

Liquids with high cohesive strength (polar)

• capable of hydrogen bonding

• interacts well with other polar liquids

• examples: water and ethanol

Liquids with low cohesive strength (non-polar)

• held together mainly by weak van der Waals forces

• interacts well with other non-polar liquids

• poorly miscible with high-cohesion liquids like water

• examples: hexane, benzene, octanol, vegetable oil

Cosolvent systems

• the solubility of a weak electrolyte or non-polar compound in water can be improved by the addition of water-miscible solvent in which the compound is also soluble

• vehicles used in combination to increase the solubility of a drug are called cosolvents

Dielectric constant

• the solubility of a drug is generally affected by the dielectric constant of the solvent system

• ideally, suitable blends should possess values of dielectric constant between 25 and 80

• the dielectric constant of a mixed solvent system can be approximated by the weighted average of the dielectric constants of the individual solvents

How do cosolvents help to improve solubility?

• co-solvents increase the solubility of non-polar solutes in water

• water is highly structured because water molecules are linked by a hydrogen-bonded network

• for a solute (drug) to dissolve, a solute must make room in water, which means disrupting the hydrogen-bond network

• this reduces the entropy penalty of dissolving the solute

pH control

• if a drug is either a weak acid or weak base, its degree of ionization and consequently its solubility are influenced by the pH of the solution

• in controlling the solubility of the drug this way, we must ensure that the chosen pH does not conflict with other product requirements

Solubilization

• the solubility of a drug in water can be improved by the addition of a surfactant

• the concentration of surfactant used should be above its critical micelle concentration (CMC)

• however, a large excess of surfactant is undesirable

• factors that affect the choice of solubilizing agent - toxicity and irritancy, miscibility with solvent system, compatability with other components, odor and taste

Anatomy of a surfactant

hydrophilic head and hydrophobic tail

Types of surfactants

Nonionic

• span

• tween

• cremophor EL

Ionic

• sodium dodecyl sulfate

• cetrimonium bromide

How do surfactants improve aqueous solubility?

surfactants form micelles that provide an environment to solubilize lipophilic molecules

Complexation

• the complexation process involves the interaction of a poorly soluble drug with a soluble material to form a soluble complex

• the bonding between the components is normally weaker than a covalent bond

• complex formation should be easily reversible as most complexes are macromolecules which tend to be inactive

• examples: metal, organic molecular, inclusion

How does complexation result in increased solubility?

• a ligand is a molecule that interacts with another molecule, the substrate, to form a complex

• drug molecules can form complexes with other small molecules or with macromolecules such as proteins

• once complexation occurs, the physical and chemical properties of the complexing species are altered

• complexation is a reversible process

• the complexing agent sequesters the drug (reduces the “free” drug concentration), allowing the total amount of drug in the system to be increased

Metal complexes

• a metal ion bound to ligands, which donate electron pairs (usually from O, N, or S)

• chelates: one ligand binds at several points, forming a ring, which makes the complex more stable (ex. EDTA)

• complexation can increase solubility (IV iron, gadolinium) or decrease it (tetracyclines with Ca, Mg, Al, Fe)

Metal complexes that reduce solubility (tetracyclines)

• stable chelate complexes are formed by tetracyclines with many metals, including calcium, magnesium, and iron. such chelates are usually insoluble in water

• side effect: irreversible staining of teeth (the complex is yellow and with ligh exposure it oxidized over time to brown or gray)

Metal complexes that reduce solubility (fluoroquinolones)

• fluoroquinolones are another class of antibiotics that chelate metal complexes

• the chelate forms in the gut and is poorly soluble and poorly absorbed, so antibiotic levels drop. the effect can be large

• culprits: antacids, calcium and iron supplements, multivitamins with minerals, and dairy or calcium-fortified juice when taken alone

Organic molecular complexes

type of interaction

• charge-transfer interaction (lone pair electrons from povidone to iodine)

resulting properties:

• the complex is water-soluble, unlike elemental iodine

• it slowly releases free iodine → antiseptic action

• appears brown in color, typical of povidone-iodine solutions

Cyclodextrins - solubility enhancing inclusion complexes

cyclic glucopyranose structures with polar exterior surfaces which provide for enhanced water solubility and non-polar core surfaces with enhances interactions with non-polar regions of guest molecule

Cyclodextrin complexes

• cyclodextrins form a guest (drug) - host (cyclodextrin) inclusion complex

• more than one cyclodextrin molecule can be associated with a single drug molecule

• cyclodextrins are found in oral and injectable solutions

Chemical modification

• this involves synthesis of solubles salts of the drug

• the soluble salt which may not have any activity is converted back to the active free form in the biological system

• examples; sodium phosphate salts of hydrocortisone, prednisolone, and betamethasone, sodium succinate salt of chloramphenicol

Particle size reduction

• the size and shape of very small particles can affect their solubility

• particle size is commonly reduced by milling

• the method is less commonly employed to improve solubility for liquid dosage forms

Colligative properties of solutions

• in chemistry, colligative propertires are properties of solutions that depend only on the number of solute particles bound together in the solvent - not on their chemical identity

• that’s why we call them “colligative” - the term emphasizes that the effect is collective, determined by how many solute particles are bound up in the solution system, not what those particles are

• boiling point elevation, freezing point depression, vapor pressure lowering, osmotic pressure

Osmotic pressure

• water passes through semi-permeable membrane from a region of higher water concentration to a region of lower water concentration

• the amount of pressure required to stop osmosis

Tonicity

effective osmotic pressure of a solution relative to a body fluid determined only by solutes that cannot cross biological membranes

Isosmotic

two solutions with equal osmotic pressures

Isotonic

• solution with the same osmotic pressure as a specific body fluid

• 0.9% sodium chloride is isotonic

Hypertonic

• a solution with higher osmotic pressure than a body fluid

• water will leave blood cell, cell will shrink

Hypotonic

• a solution with lower osmotic pressure than a body fluid

• water will swell into blood cell

If I dissolve 1 mole of salt (NaCl) in water, do I really get just 1 mole of particles in solution?

• NaCl → Na+ and Cl-

• we get two moles of particles when NaCl dissociates

• however, due to the solvation of the ions and other “non-ideal” intermolecular interactions, the effective “dissociation value” is ~1.8

• that is why we need a correction factor - the van’t hoff factor, to tell us how many particles are formed per formula unit in solution

• most of the time, dissociation is not complete, maybe 80%

Osmol

• the weight, in grams, of a solute that is osmotically equivalent to a mole of an ideally behaving nonelectrolyte (estimate by MW and # of dissociable species)

• 1 mol of NaCl → 2 Oslo

mOsm

• milliosmole

• 1/1000th of an osmol

Osmolality

osmol/kg of solvent

Osmolarity

osmol/L of solvent

Preparing isotonic solutions using freezing point depression

• for a compound with minimal/no dissociation in water, when one mole of solute is dissolved in 1000g of water, the freezing point is decreased by 1.86 C

• over small temperature ranges, the freezing point depression as a function of solute concentration is linear/proportional

E-value

grams of NaCl that produce the same osmotic effect as 1 gram of the drug or solute

Bioburden

the number of viable microorganisms present prior to sterilization

Vegetative microorganisms

actively growing microbes

Pyrogens

• substances which, upon entering the bloodstream, will cause a variety of symptoms, the most recognizable of which is fever

• endotoxins are examples of pyrogenic substances of microbial origin

Sterility

• the absolute absence of viable microorganisms

• sterility is an absolute term. either something is sterile, or it is not

Sterilization

a process by which all viable microorganisms are removed or destroyed

Terminal sterilization

• a process used to render products sterile to a preferred sterility assurance level

• terminal sterilization is the preferred method for parenterally-administered pharmaceuticals

• however, it is not suitable for all types of products, so filtration through a bacteria retentive filter and aseptic processing is also used

Factors affecting sterilization

number and location of microorganisms

• if all other conditions remain constant, the larger the number of microorganisms then the longer the sterilization process is required to run, in order to destroy all microorganisms present - meticulous cleaning and disinfection are highly desirable

• aggregated or clumped microbial cells are more difficult to inactivate than mono-dispersed cells - poor penetration of sterilants

innate resistance of microorganisms

• spores are generally the most resistant to sterilization processes, because the spore coat and cortex act as a barrier

Gas Sterilization

usually carried out in a pressurized chamber similar to steam autoclave but with additional unique features to sterilizers employing each gas along with an appropriate degassing system

Gas Sterilization - ethylene oxide

characteristics

• highly reactive, alkylating, toxic, flammable, explosive

mechanism of action

• alkylation leads to the blocking of many reactive groups needed in essential metabolic reactions

advantages

• material compatability (unlike heat and radiation), it is unlikely to cause polymer degradation or physical and mechanical changes to the product

• a low temperature sterilization technique

• can perform repeated sterilization cycles without the risk of damaging the product

disadvantages

• leaves toxic residues and by-products like ethylene glycol and ethylene chlorohydrin

• causes cancer to animals exposed via inhalation

• a possible human carcinogen

• might react with human DNA and cause inheritable mutations

applications

• sterilizing disposable medical devices

• heat-sensitive pharmaceuticals, cosmetics, and food

Gas Sterilization - chlorine dioxide

mechanism of action

• ClO2 gas is a single-electron transfer oxidizing agent that can destroy the cellular activity of proteins

advantages

• a potent oxidizing agent

• has disinfecting and sterilizing capability is water

• effective at room temperature and atmospheric pressure

• sterilization cycles are short

• relatively inexpensive

• non-mutagenic and non-carcinogenic

disadvantages

• ClO2 is an unstable free radical which makes it unsuitable for storage for later use. it must be generated in situ and used immediately

• poor ability to penetrate materials

applications

• medical devices and laboratory equipment

• decontaminate clean rooms

Gas Sterilization - hydrogen peroxide vapor

replaces toxic ethylene oxide

requires a very lowe vapor phase hydrogen peroxide concentration for sterilization

mechanism of action

• direct interaction of the vapor with cellular components

• produces hydroxyl and hydroperoxyl radicals that can attack cell walls and membranes

advantages

• low temperature sterilization

• the degradation products are water and oxygen

• relatively low cost

• efficient surface sterilization

disadvantages

• cannot penetrate most surfaces

• only effective as an external surface sterilant

applications

• decontamination of cleanrooms and isolators

Moist heat sterilization

four types

• saturated steam

• steam-air mixtures

• prevacuum high temperature steam

• superheated steam

saturated steam process is carried out in a pressure vessel (autoclave)

time, pressure, and temperature are the most critical factors

mechanism of action

• direct and/or indirect contact of the steam with the product or the product surface

• denaturation of critical protein material essential for the growth and/or reproduction of microorganisms

Moist heat sterilization - saturated steam

Advantages:

• Convenient, reliable, relatively inexpensive, simple, non-toxic, fast

• Has high lethality and will destroy all types of microorganisms, including highly resistant spores, within 15 min at 121°C at a pressure of 15 psig

Disadvantages:

• Not compatible with many materials that are heat- and/or moist heat-sensitive

• Inability to penetrate certain packaging materials, very dense materials, and certain non-polar materials, such as fats, greases, and oils

• Air can interfere with the penetration of water vapor, especially in porous items

• Ineffective for anhydrous conditions, such as within a sealed ampule containing a drug solid or an anhydrous oil

Applications:

• Parenteral aqueous solutions

• Bacteriological media

• Surgeon’s gloves

• Fermentation tanks and glassware

Dry Heat Sterilization

Performed in specially designed ovens

Applies a temperature of not less than 250°C for effective depyrogenation

Mechanism of action:

• Conduction → heat is absorbed by the exterior surface of an item then passed inwards to the next layer

• Causes loss of moisture and denaturation (coagulation) of proteins

• Possible incineration of microbial cells

Advantages:

• Applied to heat-tolerant materials like metal, glass, grease, and oils

• Destroys pathogens and pyrogens (destruction or inactivation of endotoxins)

• Safe and reliable and leaves no chemical residue

• Higher penetration as compared to moist heat

Disadvantages

• High temperatures may damage materials

• Higher temperature and longer time requirements as compared to autoclaving (An exposure to dry heat at 160°C for 60 min is approximately the equivalent exposure

to moist heat at 121°C for 10–15 min)

• Not useful for aqueous materials

Resistance:

• Some bacterial spores are resistant to dry heat, thereby requiring higher temperatures for longer times (Spores of Bacillus anthracis require a temperature of 140°C for 3 h to ensure

their destruction)

Applications:

• Containers intended for intravenous solutions

• Some powders

• Some oil-based injectable pharmaceuticals

• Glassware (e.g., vials and ampules) before being aseptically filled

Sterilization by UV Radiation

mechanism of action

• UV light absorbed by microbial cells, leading to dimerization of DNA → impaired replication

• UV light does not necessarily kill the microorganisms; instead, it renders them harmless

two factors determine the inactivation of microorganisms by exposure to UV light

• intensity of the radiation

• time

limitations

• limited penetration → clumps of microorganisms and dust-covered microorganisms have limited susceptibility

• UV-induced DNA damage can be repaired by many organisms

Sterilization by y-irradiation

desirable when materials cannot withstand heat, and when there are safety concerns regarding the use of gas sterilization

mechanism of action

• damages cellular DNA/pathogen

• radiation ionizes the material it strikes by stripping electrons from the atoms of the exposed surfaces

advantages

• low chemical reactivity and possibly minimal product degradation

• low measurable residues

• fewer variables to control

disadvantages

• loss of material strength due to degradation

• color change and/or odor generation - chemical/covalent changes

applications

• contact lens solutions and some anticancer drugs

• intravenous administration sets

• plastic hypodermic syringes

Sterilization by electron beam irradiation

mechanism of action

• high energy electron beam penetrates microbial cells leading to DNA damage and microbial death

• disruption of cellular mechanisms leading to formation highly reactive intracellular

advantages

• short process cycle times

• low impact on the structure of plastics

• more control of sterilization doses can be acheived than with gamma irradiation

• unlike active gamma radiation source, it can be switched on and off when desired

disadvantages

• low surface penetration

• suited for materials of no more than 3 cm in thickness

• breakdown of packaging materials at high energy levels

• creation of free radicals from polymeric materials

applications

• medical devices and plastic disposable items

• some combination products e.g., simple adhesive bandages that carry antibiotics in wound dressings and prefilled syringes

Sterilization by filtration

physical sterilization method that involves using microbial retentive materials (filters) for microorganism removal

0.2 μm exclusion filters are the standard for sterilization process

Microorganisms can be removed by one or more of the following:

• Pore size exclusion

• Adsorption on or within filter matrix

• Physical entrapment within pore

Advantages:

• Suitable for sterilization of heat-labile solutions

Disadvantages:

• Low flow rates

• Difficulty in cleaning

• Filters may shed materials into the filtrate

• Filter integrity needs to be checked after sterilization

Some considerations for sterilization by filtration

High viscosity impedes flow

• High concentration proteins

• Addition of thickener to the formulation

High salinity (>>150 mM) solutions can cause organisms to shrink due to osmotic pressure differences, leading to a retention problem

Multiple and/or extended use of filters can lead to microbial growth within the filter and these new microorganisms can pass with the filtrate, i.e., “growth-through” problem

Challenging formulations include those containing micelles, some liposomes and nanoparticles, emulsions, and solutions containing surfactants such as PEG or Tween 80, especially if other “plugging” ingredients such as proteins are also included in the mixture.

Aseptic

Refers to areas and practices where the intent is to be sterile

Aseptic processing

Those operations performed between the sterilization of an object or preparation and the final sealing of its package. These operations, by definition, are carried out in the complete absence of microorganisms

Since there is no terminal sterilization, products that are aseptically filled are at higher risk of contamination

Possible sources of contamination

Water

• Minimize its use

• Use pharmaceutical grade water (water for injection)

• Keep areas dry

Air

• Use air filters

• Minimize the amount of packaging that enters the clean room (microbe in the air can settle on these surfaces)

Transferring items in and out of a clean room (e.g., trolley wheels that are not correctly sanitized)

Surfaces (within room and from equipment)

Personnel (most significant source of contamination)

• Use unidirectional air flow, isolators, and solid barriers

• Use appropriate clothing

Sterilization of complex pharmaceuticals

Some solid dosage forms, such as antibiotics which are unstable in solution are manufactured aseptically

Colloids, suspensions, and emulsions that are thermolabile may require each of the individual components to be sterilized separately with the product being formulated and processed under aseptic conditions

Ointments:

• Plastic tubes for ointments are generally sterilized by radiation or ethylene oxide

• Ointment bases are commonly sterilized by filtration at sufficiently high temperature to ensure fluidity

Ophthalmic and inhalation products:

• Prepared using the blow-fill-seal technology

Preservatives in solution formulations

Used in preparations that, while sterile when manufactured, require additional antimicrobial preservative to maintain sterility throughout the use period

May be used in non-sterile preparations also, especially those that need to maintain low bioburden during use period.

Characteristics of preservatives and preserved solutions

Preservative should be soluble at its effective concentration in the preparation

Preservative should not affect the safety of the preparation following administration

Preservative should not affect the stability of other agents in the preparation or its container

Product selection and sterility awareness

Vancomycin injection must be sterile, as it’s given intravenously.

It’s prepared from a powder for injection that is reconstituted with sterile water under aseptic conditions.

If the solution appears cloudy or particulate matter is present, it may have lost sterility or stability — and should not be used.

The pharmacist checks that the vial and diluent are sterile, unopened, and properly stored. They also ensure the final solution will be prepared in a laminar airflow hood by trained staff

Compatibility and stability

Some drugs can’t be autoclaved (heat-sterilized) because they degrade.

Vancomycin solutions are heat-sensitive, so they are sterilized by filtration during manufacturing.

When reviewing reconstitution instructions, the pharmacist confirms the manufacturer’s sterilization method and ensures no heating step is applied during preparation.

Preventing infection and contamination

A nurse asks if the reconstituted vancomycin can be used for multiple patients.

The pharmacist knows:

• Once a vial is opened, sterility cannot be guaranteed over time.

• Using it for multiple patients increases infection risk.

The pharmacist explains that each vial is single-use only to maintain sterility and prevent nosocomial infections.

Clinical oversight and education

As pharmacist, you are sometimes required to conduct a short teaching session with nursing staff, emphasizing:

• Why IV antibiotics must remain sterile.

• The importance of using sterile diluents and equipment.

• Recognizing signs of contamination (e.g., discoloration, particulates).

Educate other healthcare colleagues on the importance of sterility to lower the risk of bloodstream infections from contaminated infusions.

How are drugs determined to be generic drugs?

brand

• no difference in active ingredient

• higher in cost

• covered if no generic form exists

• tested and approved by FDA

• no difference in strength/dosage

• drugs are standard in size, color, packaging, etc.

generic

• no difference in active ingredient

• lower in cost

• normally always covered

• may differ, but proven to be acceptable by the FDA

• no difference in strength/dosage

• packaging and the drug itself may look different

A generic/therapeutically equivalent drug is approved by the FDA if it is…

• Approved as safe and effective

• pharmaceutically equivalent in that it (a) contains identical amounts of the same active drug ingredient in the identical dosage form and route of administration and (b) meets compendial or other applicable standards of strength, quality, purity, and identity. (They may differ in characteristics such as shape, scoring, packaging, excipients (colors, flavors, preservatives), expiration time, and labeling.)

• Are bioequivalent in that it (a) does not present a known or potential bioequivalence problem and it meets an acceptable in vitro standard (usually dissolution testing) or (b) if it does present such a known or potential problem, it is shown to meet an appropriate bioequivalence standard

• adequately labeled

• manufactured in compliance with current Good Manufacturing Practice regulations

What can be different between pharmaceutically equivalent drug products?

• Pharmaceutical equivalents must deliver identical amounts of the active ingredient over the identical dosing period, but they do not necessarily contain the same inactive ingredients.

• They may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration date/time, and within certain limits, labeling.

Bioavailability

Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of drug action.

Bioequivalence

Bioequivalence is the absence of a significant difference in the rate and extent to which the active drug ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

Bioequivalence criteria

Two drug products are deemed bioequivalent if the 90% confidence intervals of the geometric mean of the (generic/innovator) test ratio (C max or AUC) fall within the bioequivalence limits of 80-125%.

90% Confidence Interval

90% confidence that the parameter estimate will fall within the interval

Why geometric mean?

Area under the curve (AUC)

• Data are log transformed to accommodate the expected log-normal distribution of biological outcomes

• AUC = (F x D)/(V x k e ) suggests a multiplicative relationship best described by the geometric mean

F: Bioavailability

D: Dose

V: Volume of distribution

ke: Elimination constant

Why 80 to 125%?

Medical experts believe that, for most drugs, a ± 20% difference in concentration ofactive ingredient in the blood will not be clinically significant

Sources of variation in BE testing (in vivo and in vitro)

• Normal vs. disease-state patients

• Interpatient variability (weight, age, sex, race,…)

• Content uniformity of dosage form

• Release and subsequent absorption of drug from dosage form

• Correlation of dissolution rate to absorption rate when using dissolution as a surrogate test method

• Variability in experimental measurements for all data

Alternatives to bioequivalence (human C max, AUC) testing

Pharmacodynamic response (surrogate marker)

• Inhaler (forced expiratory volume)

• Eye drop (intraocular pressure)

In vitro testing

• Disintegration testing

• Dissolution testing

BCS drug classification system (categorizes drug compound based on solubility and permeability)

• dissolution testing

• permeability testing

FDA therapeutic equivalence evaluation

Approved Drug Products with Therapeutic Equivalence Evaluations (aka Orange Book)

• “A _” rated drugs: considered therapeutically equivalent and may be interchanged.

• “B _” rated drugs: inadequate evidence of bioequivalence and should not be interchanged

Therapeutic equivalence code

AA Products in conventional dosage forms not presenting bioequivalence problems

• Multisource drug products coded as AA contain active ingredients and are in dosage forms that are not regarded as presenting either actual or potential bioequivalence problems or drug quality or standards issues. However, all oral dosage forms must, nonetheless, meet an appropriate in vitro bioequivalence standard that is acceptable to the Agency in order to be approved.

AB, AB1, AB2, AB3... Products meeting necessary bioequivalence requirements

• Multisource drug products listed under the same heading (i.e., identical active ingredients(s), dosage form, and route(s) of administration) and having the same strength generally will be coded AB if data and information are submitted demonstrating bioequivalence.

• In certain instances, a number is added to the end of the AB code to make a three-character code (i.e., AB1, AB2, AB3, etc.). Three-character codes generally are assigned only in situations when more than one RLD of the same strength has been designated under the same heading.

• f a study is submitted that demonstrates bioequivalence to an RLD, the generic drugproduct will be given the same three-character code as the RLD it was compared against.

Using science to choose the right product

We can tune the release kinetics (input) to target a certain pharmacokinetic profile.

• Drug release rate can be modified (input kinetics) to tailor the plasma concentration vs. time profile (pharmacokinetics) for a specific outcome.

Kinetic barriers to drug absorption for oral solids

The processes of disintegration and dissolution are kinetic processes that affect how long it takes for the drug molecule to enter blood circulation.

These kinetic processes directly influence the pharmacokinetics of a drug.

Mainly, we are concerned with

• How quickly a pharmacological effect is initiated;

• For how long is the pharmacological effect maintained (affects dosing frequency).

Solubility and permeability

Both solubility and permeability affect C max and T max.

• This is one reason why our BCS classification system is built on the interplay of these two properties

Disintegration

The process of breaking the tablet into smaller pieces (very literal); does not capture the process of drug dissolving

Dissolution

The process of a solid (e.g., drug) entering solution (dissolving) → directly affects the concentration of drug in solution/GI tract

Solubility component

Dissolution rate: (Noyes-Whitney Eq.) → dC/dt = KS(Cs - C)

• K = the dissolution rate constant

• S = surface area of the solid

• Cs = solubility of the solid

• C = concentration of drug in solution at time, t

solubility and surface area are factors that we can modify

Modifying the surface area term

The size of particles can be reduced through milling.

Caveat

• Absorption is influenced by 2 kinetic properties: dissolution and permeation.

• IF absorption is permeation-limited, strategies to enhance dissolution rate (e.g., particle size reduction) will not provide a significant improvement in bioavailability.

• IF the dissolution is rate-limiting, particle size reduction can help improve bioavailability.

Modifying the solubility term

Beginning with the “solid” in oral solids, there are a variety of forms or solids phases that may selected for the active pharmaceutical ingredient (API).

Remember, everything in a drug product (from the API to the secondary packaging) is included deliberately.

Selecting the appropriate solid form, the main considerations are:

1. Solubility

2. Stability

3. Processability

Crystalline solids

A unique property of crystalline solids is periodicity, i.e., one building block (the unit cell) may be repeated in space (in 3-dimensions) to create the entire solid

Polymorphism

Changing that arrangement yields a different polymorph, and changes directly the physical properties of the solid drug: dissolution, compaction, kinetics, bioavailability, etc.

Note that it’s not the chemical identity that’schanging, it’s the crystalline structure and the intermolecular interactions.

Controlling polymorphism is a multi-billion-dollar challenge to the pharmaceutical industry.

Solubility of different polymorphic forms

Since the intermolecular interactions are different in different polymorphic forms of a solid, they typically have different solubility values.

Why?

• For a solid crystal to be soluble, its lattice needs to be broken apart.

• The energy required to break the lattice apart is different for different polymorphs, which translates into different solubility values.

Stability of different polymorphic forms

By convention, stabilizing energies are represented as a negative value.

A more stable lattice (think stronger intermolecular interactions) has a more negative lattice energy.

From a solubility perspective, that means the more stable a polymorph, the more energy you have to put in to break the lattice apart, i.e., more stable = less soluble

more stable lattice, higher melting point, less soluble.

Amorphous form

Amorphous is a unique solid form that has no long-range order, i.e., no periodicity.

This is a notoriously unstable (high energy) solid form.

• Less stable than the most unstable crystalline polymorph.

However, the “advantage” of being so unstable is that amorphous materials can display a significant solubility advantage.

Amorphous solids

An amorphous form could be prepared from a crystalline drug through different techniques.

Milling

• Primarily used to reduce particle size, but during the process you introduce defects (imperfections) in a crystal.

• Continue to add more and more defects, you reduce the long-range order to the point you get an amorphous.

• Stability is the main drawback to formulating amorphous solids (hygroscopicity concern)

Melting/quench cooling

• Crystalline solids can be heated above their melting points and quickly quenched cooled.

• Example of amorphous solid prepared via melt/cool method: glass (quartz sand heated to > 3,090 °F) and cooled.

Amorphous solid dispersion

Role of the polymer:

• Stabilize the amorphous drug during storage (prevents conversion back to the crystal form).

• Stabilize the amorphous drug in solution to maintain the solubility advantage.

• Enhance drug dissolution rate during dissolution (relates to bioavailability).

Marketed amorphous solid dispersion products

Prior to 2005, there were a few ASDs, but they have continued to emerge at a faster rate, in part because many emerging drug candidates are BCS II or IV.

This trend is going to continue as more drugs in the development pipeline have poor aqueous solubility

Definition of co-crystal

Co-crystals have been around for 100 years but only recently have demonstrated significant potential.

Working definition of co-crystal is, “a solid that is crystalline single-phase material composed of two or more different molecular or ionic compounds in a stoichiometric ratio which is neither a solvate or simple salt”.

To be considered a co-crystal,

• 1. The components (API and co-former(s)) are in a fixed stoichiometric ratio (1:1, 1:2, 1:2:1).

• 2. The API and co-former(s) are separately solids at room temperature.

• This is what distinguishes a co-crystal from a solvate.

A benefit of co-crystals is that even the most stable phase can still display a 1000× solubility advantage

Co-crystal: Strengths and challenges

The limitation is what co-former do you choose.

To improve the solubility, one hypothesis is to use a water soluble co-former.

We’re re-arranging the intermolecular interactions (like polymorphs or amorphous forms), but now also introducing another species.

Thus, heat of solvation may be affected too.

Higher co-former solubility = higher co-crystal solubility (relative to the pure drug)

Modifying the permeability term

Most drugs delivered orally rely on passive diffusion for uptake.

However, peptides and biologics (e.g., GLP-1 analogues) are usually too large and hydrophilic to permeate → poor oral bioavailability.