Preformulation Studies and Drug Optimization

Preformulation Studies

• It is essential to ensure the new drug is safe and effective
• It also needs to be available at the site of action in the correct form and dosage
• This is achieved by considering the physical, chemical, analytical, pharmacokinetic and pharmacodynamic properties of the drug

Optimization of Active Molecular Entities

• After pharmacological screening, the correct molecular form of the active entity must be ascertained
• Optimization is needed for stability under environmental conditions and enhanced performance

Salts

• Nearly half of all drugs are administered as salts
• Converting a molecule to a salt is a common method to enhance performance and properties like solubility, bioavailability, stability, organoleptic properties, patient compliance and modify release
• The type of formulation that is being developed will determine the best salt form
• If developing a tablet, solution, or injectable, sodium and hydrochloride are the most suitable forms as they enhance solubility
• Naproxen's water solubility is increased severalfold when converted to a sodium salt
• Tolbutamide has 1000-fold greater water solubility than its free acidic form
• For suspensions, insoluble salt forms like tosylate, estylate, and embonate are better
• For hypertension treatments, sodium or potassium salts should be avoided
• Diclofenac potassium is favored over sodium salt for analgesic use in patients with hypertension, toxicity and regulatory requirements need to be met.
• Lithium salt should be strictly avoided
• Sodium or hydrochloride salts are generally preferred for immediate-release formulations as they show better solubility
• For delayed release, low solubility salts such as tosylate, estylate, and embonate can be used
• Converting to a salt form improves patient compliance
• Cephalosporin pain at injection sites can be reduced with morpholine salt
• Piperazine's taste can be improved by converting it into a salt with adipic acid

Prodrugs

• A prodrug is a chemically modified, inactive form of a drug that is optimized for in vivo performance, with the aim of improving bioavailability via avoiding first-pass metabolism
• Prodrugs undergo biotransformation into their active form to have a pharmacological effect which depends on the specific drug property
• "Cod drugs" contain two pharmacologically active components in a single molecule like sulfasalazine
• "Soft drugs" are modified derivatives with predetermined metabolism to avoid toxicity
• "Hard drugs" are modified to retain original properties and avoid chemical or biological transformation
• Carrier-linked prodrugs link the drug to a carrier moiety by a temporary covalent linkage to generate a more bioactive molecular entity like carrier molecule or functional group
• Bioprecursor prodrugs are a result of molecular modification of the active principle yielding a new metabolite after in vivo transformation
• Prodrug development improves water solubility, lipophilicity, chemical stability, and organoleptic characteristics

Improving Pharmacokinetics

• Prodrug helps with improving bioavailability, improving penetration power through membranes, improving first-pass metabolism and enabling target-specific drug delivery.

Target-Specific Delivery Via Prodrugs

• Capecitabine is a prodrug of 5-fluorouracil that requires a triple-phase transformation and is used in metastatic colon cancer.
• Sulfasalazine is converted to sulfapyridine and 5-amino salicylic acid in the colon through bacterial reductase action, which is another example of target-specific delivery
• Esterification increases lipophilicity
• Terbutaline requires a lower dose than terbutaline because its prodrug, bambuterol increases lipophilicity and chemical stability

Determining Chemical Properties

• It indicates the absorption behavior and stability of a molecule in the body
• Key properties include partition coefficient (Log P), dissociation constant (pKa or pKb), and stability under different conditions which each play a role in formulation development

Partition Coefficient

• The Log P value is the ratio of unionized drug distributed between aqueous and organic phases
• The oil-water partition coefficient shows a medications ability to cross the lipidic membrane
• The lipophilic/hydrophilic balance is a key contributing factor to optimum drug absorption, which makes the unionized version the most important
• LogP = (oil/water) equilibrium ....E1
• If the Log P value is 0, the drug has equal distribution
• Values less than 1 indicate higher water solubility
• Values greater than 1 indicate higher lipidic solubility so a proper balance is required.
• Log P is determined using shake flask method, chromatographic method (HPLC), software computation, and countercurrent/filter probe method
• The shaking flask method utilizes an octanol-water system to determine drug partitioning behaviors.
• Octanol mimics the lipoidal character of biological membrane and contains a polar head and nonpolar tail.
• Octanol is immiscible with water
• The solubility parameter for most drugs is similar to octanol

Dissociation Constant

• Like partition coefficient, the dissociation constant (pKa) determines solubility
• pKa value determines the extent of solubility in pH-dependent environments and the extent of ionization as only unionized forms are absorbed.
• pKa indicates site of absorption
• Weakly acidic drugs with pKa around 4 are best absorbed from the stomach
• Basic drugs with pKa around 8 are best absorbed from the intestine as they are predominantly unionized.
• %Ionization={10(pH−pKa)/1+10(pH−pKa)}×100% …E2.
• Strong acids and bases are largely ionized in the GIT and are poorly absorbed
• Most pharmaceutical entities are derivatives of weak acids and weak bases, so their absorption is not an issue.

Chirality

• Isomer type is a chemical parameter impacting the pharmacological activity of the molecule.
• Many molecules are in racemic form, which means they can be either laevorotatory (-) or dextrorotatory (+)
• Only one form gives the desirable result
• Other isomers may be devoid of desirable effects or may exhibit deleterious side effects and can give disastorous consequences
• Single enantiomers dominate due to better pharmacological performance,
• Racemic or chiral switching is used in which racemic mixtures are developed as single enantiomers like levofloxacin, esomeprazole, escitalopram, and desloratadine
• Chirality uses optical rotatory dispersion and circular dichroism

Stability

• Determines the conditions in which the molecule deteriorates
• Determines the degradation pathway
• The mechanism of degradation helps to design formulation, suitable molecular modification, storage condition, and packaging correctly
• Molecules undergo degradation via hydrolysis, oxidation, photolysis, and racemization
• Hydrolysis is studied after oxidation

Hydrolysis

• Hydrolysis involves reaction of a molecule with water to cause cleavage of a chemical bond
• Readily hydrolysable functional groups speed the reaction up making the molecule ineffective.
• Molecules containing esters and amide functional groups are prone to hydrolysis which may lead to formation of a carboxylic acid or an alcohol.
• Effectiveness rely on hydrolytic stability of the molecule
• Lidocaine is an amide derivative of procaine and is used as a local anesthetic
• Ester derivatives hydrolyze more readily, amide derivatives are more stable making them long acting.
• Beta-lactam antibiotics go through hydrolysis and are supplied as dry powder injections to be reconstituted before use

Oxidation

• Involves exposure of a molecule to atmospheric oxygen or autoxidation by free radicals, however some oxidation is initiated in presence of light or elevated temps.
• Light exposure and temperature are controlled during storage
• Antioxidants are added
• Oxidation can be studied by passing oxygen through a substance, or hydrogen peroxide can be added

Photolysis

• Decomposition of a molecule via absorption of energy when exposed to light including shorter wavelengths
• Photodegradation can be triggered by light
• Storage, packaging, and handling conditions are adjusted based on photochemical behavior in ranges of 200-290, 290-320, 320-400, and 400-700 nm
• For example, vitamin B12 and riboflavin are susceptible to light induced oxidation
• Storing formulations containing B12 and riboflavin in amber vials blocks ultraviolet radiation to avoid decomposition

Racemization

• The event where an optically active molecule becomes inactive without any change in molecular composition where its study is important when using a racemic mixture form.
• Racemization leads to loss of pharmacological action or enhances toxic effect
• It is affected by pH, solvents, light, and temperature so studies are conducted to design optimum conditions

Physical Characterization

• New chemical entities are often in solid form
• Properties studied are bulk and micromeritic
• Bulk properties: polymorphism, crystallinity, density, deliquescence, and hygroscopicity
• Micromeritic properties: particle size, shape, porosity, and density.
• Most new chemical entities are solids and exist either as amorphous or crystalline forms which both give the main virtues: stability and solubility.

Solubility

• It is a widely studied technique in preformulation analysis and is the backbone study for determining performance of developed formulation
• Solubility and permeability form the scientific basis of the biopharmaceutics classification system (BCS), which designs a drug delivery system.
• Drug solubility is the amount of drug that dissolves in a solvent to produce a saturated solution at a constant temperature and pressure that relies on properties like characteristics, temperature, pH, complexation and molecular structure for effective oral formulation and absorption
• Improve solubility by chemical modification, using a cosolvent or surfactant, particle size reduction, hydrotropy, and complexation
• Solubility determined by amount of solvent required, and described as very soluble, freely soluble, soluble, sparlingly soluble etc

Crystal Form

• Amorphous drugs feature random molecules/atoms for higher solubility and dissolution
• Polymorphic form that faces challenge of stability to overcome poor bioavailability and clinical response caused by low water solubility.
• Crystalline forms show regular spacing making the properties of water solubility less than amorphous but impeccable stability
• Study crystallinity by X-ray, differential scanning microscopy, differential thermal analysis, hot stage microscopy, and scanning electron microscopy

Polymorphism

• Molecules can crystallize in multiple forms (polymorphs) with different internal arrangements dependent on temperature, solvent, and time
• Polymorphs main differ with respect to their physical and pharmaceutical properties, stability, activity etc
• Identification of crystal forms for each drug is required
• Chloramphenicol palmitate exits as forms A,B, and C
• B shows higher solubility, where A shows high stability
• Controlling crystal size causes caking in oxyclozanide suspensions
• Polymorphs can be crystalline or amorphous
• Solvates are molecules incorporate into a structure,
• Hydrates incorporate water
• Pseudo-polymorphs are crystal forms of solvates, also called solvomorphism
• Study pseudo-polymorphs by hot stage microscopy
• True polymorphs form a globule, psuedo-polymorphs give a bubble from vapor during melting

Hygroscopicity

• Defined as the capacity of a compound to absorb atmospheric moisture depending on atmospheric conditions and surface area
• Deliquescent substance absorbs more moisture and liquefies
• Changes in moisture influence chemical stability, flowability, and compressibility
• Hygroscopicity defined in the European Pharmacopeia under 24-hour storage at 25 degrees C and 80% relative humidity as slightly hygroscopic, hygroscopic, and very hygroscopic

Testing

• Test by exposing samples to controlled relative humidity
• Use saturated aqueous salt solutions
• Link flowability and relative humidity by amount of moisture uptake
• Moisture level uptake can be monitored by TGA (thermogravimetric analysis), Karl Fischer titration, and chromatography

Particle Size

• Greatly impacts dissolution rate, solubility, bioavailabilty, content uniformity, and lack of of grittiness
• Improve solubility by reducing particle size to increase surface area
• Suspension requires correct particle size for stability and quality
• Too much reduction creates charged particles causing instability
• Larger particles lead to caking.
• Nonuniform particle size distributions leads to content uniformity risk in potent formulations
• Determined by microscopy, sedimentation rate, coulter counter method, and surface area determination by nitrogen adsorption method
• A spherical particle has maximum area and uniformity
• Irregular particle shapes work well in topical abrasives
• Alter particle shape and size method to improve formulations

Density

• The ratio of mass to volume depends on particle size and shape
• Voids are voids in bulk volume that are interparticulate, open and closed intraparticulate
• True density = total volume of soldis, measured by a helium pycnometer
• Bulk density = total volume occupied by entire powder mass, determined by placing sieved powder bulk into a cylinder
• Tapped density is determined by placing a cylinder containing a sample on tapped density apparatus, operated a set number of times until volume is attained
• Size and type of dosage form relates to the density which is the critical parameter for low potency drugs
• Solutions addressed as they relate to density, that are addressed are drugs having low density, tablet form with low density and the density difference between drugs

Flow Properties

• Impacted by factors like frictional forces, surface tension forces, electric forces, and van der Waals forces
• Drug substance powder is needed for tablet formulation
• The parameter is linked to characteristics like hygroscopicity and partile size/shape
• A material that deteriorates with increases cohesiveness affects hygroscopic material
• Irregular shapes can throw off normal properties
• Hausner ratio, Carr's index and angle of repose help determine properties

Drug-Excipient Compatibility

• Excipients provide a role in administration and stability
• Inappropriate additives can impact chemical nature, stability for lower performance
• Incompatibilities can be determined based on the final product
• Perform test to see how the ingredients interact
• Incompatibilities include change in properties, decreased potency, toxic product, physical appearance/ conversion
• Drug or exipient incompatibility results in change in the properties, being physical through breaking of bonds, changes in color, in flow traits or sedimentation rate.
• Chemical incompatibility is interaction through chemical degradation or hydrolysis
• Test by using chromatographic studies and Maillard reactions
• Assess incompatibilities with lactose and groups
• By using spectroscopic technizues and chromatography tests

This section discusses preformulation studies crucial for ensuring drug safety, efficacy, and optimal delivery. It covers optimizing active molecular entities for stability and performance. It also highlights the importance of salt selection in modifying drug properties like solubility and bioavailability.