Preformulation Studies: Drug Development

Introduction to Preformulation Studies

• Preformulation studies are crucial in formulation design, especially after a new drug entity passes toxicity screening and its benefits outweigh its side effects.
• The ultimate effect of a new chemical entity relies on its availability at the target site.
• Transforming an active drug entity into a pharmaceutical formulation is a challenge overcome by preformulation studies.
• Preformulation involves studying the physical, chemical, analytical, pharmacokinetic, and pharmacodynamic properties of a new chemical entity
• This study is multidisciplinary, involving pharmacology, toxicology, clinical pharmacy, biochemistry, medicinal & analytical chemistry.
• Preformulation aims to administer the drug correctly, in the right amount, to the right target.
• A secondary aim is to provide longer formulation stability by proper design, protecting the drug from environmental conditions and evaluating performance.

Optimization of Active Molecular Entities

• Following pharmacological screening, ensuring the correct molecular form is essential
• Optimization enhances molecular stability and performance (bioavailability/stability)
• This can be achieved through molecule modification into salts, solvates, polymorphs, or prodrugs.
• Nearly half of marketed drugs are administered as salts, which significantly enhances the molecule's performance.
• These improvements include increased solubility/bioavailability, improved hydrolytic and thermal stability, better organoleptic properties, increased patient compliance, and modified release.

Salt Considerations

• Sodium and hydrochloride salts are preferred for tablets, oral solutions, or injectables due to enhanced solubility and bioavailability.
• For example, naproxen's water solubility increases when converted to its sodium salt.
• For suspensions, insoluble salt forms like tosylate, estylate, and embonate are preferred
• Salt selection considers therapeutic indication, avoiding sodium or potassium salts for hypertension treatments and potassium salt of diclofenac is preferred over sodium salt.
• Regulatory selection must meet requirements and be non-toxic, where lithium salt use is prohibited.
• Sodium or hydrochloride salts are preferred for immediate-release, while low-solubility salts are used for delayed-release formulations.
• Converting to a salt can increase patient compliance
• Converting a molecule is a solution to cephalosporin injections that caused pain, when administered as a morpholine salt reduced pain.
• Taste and odor can be improved as well, piperazine can be converting into salt with adipic acid.

Prodrugs

• Prodrugs are chemically modified, inactive derivatives that enhance in vivo performance
• One-tenth of pharmaceutical products are prodrugs, improving bioavailability and absorption by avoiding first-pass metabolism.
• Prodrugs undergo biotransformation into active forms, improving stability/bioavailability.
• "Cod drugs" contain two active components complexed into one molecule (e.g., sulfasalazine).
• "Soft drugs" are modified for predetermined metabolism, which avoids toxicity
• "Hard drugs" have modifications that allows original properties to be retained but are not prone to metabolite generation.
• Carrier-linked and bioprecursor prodrugs are two main categories
• Carrier-linked prodrugs link a drug to a carrier moiety via temporary covalent linkage and the carrier is often biologically inert.
• Hydrolytic cleavage usually removes carrier molecules or functional groups in vivo.
• Covalent linkage between drug and carrier molecule occurs
• Carrier-linked prodrugs are less active than the parent compound
• The linkage between the drug and carrier molecule breaks in vivo
• The prodrug and transport moiety must be non-toxic
• Active generation must occur with rapid kinetics to ensure drug levels at the target site

Bioprecursor Prodrugs

• The active principle undergoes molecular modification
• A new metabolite is produced through the in vivo transformation of the drug
• Goals include improved water solubility, lipophilicity, chemical stability, and organoleptic characteristics.
• Bioavailability, membrane penetration, first-pass metabolism, and targeted delivery are improved.
• Capecitabine requires triple-phase transformation to turn into its active form 5-fluorouracil
• Bacterial reductase releases sulfasalazine in the colon
• Sulfasalazine is converted to sulfapyridine and 5-aminosalicylic, which is the product.
• Esterification improves lipophilicity.
• Terbutaline's prodrug bambuterol requires a considerably lower dose than terbutaline

Determination of Chemical Properties

• Chemical properties determine a molecules in vivo absorption and stability
• Key properties include partition coefficient (Log P), dissociation constant (pKa or pKb), and molecule stability
• Each property influences formulation development

Partition Coefficient

• Log P is the ratio of unionized drug distribution between aqueous and organic phases
• The oil-water partition coefficient indicates how well a drug crosses lipidic membranes
• Lipophilic/hydrophilic balance impacts drug absorption/delivery.
• The unionized form of a molecule is more lipophilic
• If Log P is 0, the distribution is equal in water and partition solvent; less than 1 indicates higher water solubility, and greater than 1 indicates higher lipidic solubility.

Methods

• Several in vitro methods determine the partition coefficient of a molecule
• These methods include shake flask, chromatographic (HPLC), computation using software, and also countercurrent/filter probe
• The shake flask is a highly used method that uses the octanol-water system to determine drug partitioning
• Octanol mimics the lipoidal character of biological membranes
• Octanol is immiscible with water, where some water is present in the polar head portion
• Solubility parameter for most drugs resembles octanol

Dissociation Constant

• Dissociation constant (pKa) determines solubility and ionization extent in a pH-dependent environment
• Ionization determines absorption, which is most effective when it is unionized
• pKa value determination is ideal for understanding the absorption site
• Weakly acidic drugs (pKa ≈ 4) are best absorbed in the stomach and basic drugs (pKa ≈ 8) best absorbed in the intestine due to its unionized form
• Strong acids and bases are poorly absorbed throughout the GIT as it is often ionized

Chirality

• Isomer type defines pharmacological activity
• Molecular entities exist in racemic form, but only one form gives the desirable pharmacological activity with other isomers exhibiting a deviation
• Thalidomide causes teratogenic effects however, R-enantiomer was effective as a sedative agent.
• Single enantiomers have better pharmacological performance
• Racemic or chiral switching develops racemic mixtures into single enantiomers
• Examples include: levofloxacin (ofloxacin), esomeprazole (omeprazole), escitalopram (citalopram), desloratadine (loratadine)
• It is then necessary to study molecule chirality, which can be studied by optical rotatory dispersion and circular dichroism

Stability

• Identifying deterioration conditions and degradation pathways is crucial for Stability
• Knowledge informs formulation design, molecular modification, storage conditions, and packaging
• Hydrolysis, oxidation, photolysis, and racemization mediate degradation with hydrolysis being mostly studied

Hydrolysis Reactions

• Hydrolysis involves a reaction with water
• Readily hydrolysable functional groups can speed the reaction faster which causes ineffectiveness.
• Esters and amide functional groups are hydrolysis-prone, creating carboxylic acid or alcohol.
• The effectiveness of molecule therefore depends on its hydrolytic stability
• Lidocaine is amide derivative of procaine which is more stable and lasts-longer
• Beta-lactam antibiotics are susceptible to hydrolysis, and supplied as dry powder injection

Oxidation

• Molecule exposure to O2 or autoxidation causes oxidative degradation
• Light or elevated temperature initiates cases of Oxidation
• It is controlled by avoiding exposure to lights and storage at controlled temperatures
• Oxidation can be controlled by adding anti oxidants or can be studied by flowing oxygen or hydrogen peroxide.

Photolysis

• A molecule decomposes from absorption of energy from light
• Exposure to light causes photodegradation and oxidation
• Shorter wavelength components cause more oxidation
• Prior knowledge of photochemical behavior assists in proper storage, packaging, and handling
• Photo chemical molecules are studied in the range of 200–290, 290–320, 320–400, and 400–700 nm
• Use of amber vials helps avoid decomposition and helps UV radiation blocking

Racemization

• Optically active molecule becomes inactive with no change in molecular composition
• Racemization leads to pharmacological action loss or toxicity
• It is affected by pH, solvents, light, and temperature
• The goal is to design optimum conditions for stability

Physical Characterization

• Polymorphism, crystallinity, and density are bulk properties
• Particle size, shape, porosity, and density are micromeritic properties
• Solubility and stability are key properties

Solubility Profiles

• A solubility profile is a primary test when performing preformulation analyses
• Solubility helps determine a formulations performance
• Solubility and permeability form the scientific basis of biopharmaceutics classification system (BCS), which can provide framework for designing type of drug delivery system
• Solubility is the amount of solute that dissolves in a solvent, constant temperature and pressure.
• Good aqueous solubility is required for effective oral formulations for better absorption
• Solubility depends on crystal characteristics, temperature, pH, complexation, and molecular structur
• Chemical modification, cosolvents/surfactants, particle size reduction, hydrotropy and complexation can improve solubility.

Solubility Descriptors

• Very soluble: Less than 1 part of solvent requires part of the solute
• Freely soluble: 1-10 parts of solvent requires part of the solute
• Soluble: 10-30 parts of solvent requires part of the solute
• Sparingly soluble: 30-100 parts of solvent requires part of the solute
• Slightly soluble: 100-1000 parts of solvent requires part of the solute
• Very slightly soluble: 1000-10,000 parts of solvent soluble
• Practically insoluble or insoluble: 10,000 or more parts of solvent requires part of the solute

Crystalline/Amorphous Forms

• Amorphous drugs involve randomly arranged molecules with techniques for obtaining them includes: precipitation, rapid cooling after melting, and lyophilization
• Amorphous forms have better solubility and dissolution rates, this solves problems on drugs with low water solubility
• Amorphous forms have reduced stability compared to crystalline forms
• But benefit exceeds risks
• Novobiocin's crystalline form has no therapeutic effect versus amorphous form
• Crystalline forms are characterized for regular spacing between lattices
• These have impeccable stability with lower water solubility than amorphous forms
• Penicillin G as crystalline form has better stability and therapeutic response versus amorphous form
• X-ray, differential scanning microscopy, differential thermal analysis, hot stage and scanning electron microscopy are study crystallinity

Polymorphism

• Ability of molecules to crystallize as more than one with distinct chemical
• Crystalline depends on temperature, solvent, and time
• Polymorphs differ in physical and pharmaceutical properties
• Polymorphs show different types of solubility, stability, and therapeutic activities.
• It is mandatory to identify polymorphs for drugs
• Chloramphenicol palmitate exists in in three polymorphs
• Form B has solubility and dissolution profile versus form A, which is highly more stable
• Unstable to Stable transformation cause oxyclozanide to cake
• Crystal growth causes gritty texture in creams
• Results in creams instable formulations
• Solvents (hydrates) incorporate the drug molecules which are solvates
• Also referred to as solvomorphism
• Four solovates are generated when using solvents with ethinylestradiol
• hot stage microscopy, melting behavior, and true polymorphs can differentiate between pseudomorphs.

Types of Polymorphs

• “Monotropic Polymorphs": Reversibly changed by temperature and pressure
• “enantiotropic polymorphs.”: One-time transition polymorph
• Stable polymorph is physically stable with highest melting point, lowest energy, and least aqueous solubility
• Metastable polymorph has wider application but suffers from stability issues

Hygroscopicity

• Hygroscopicity is defined as the capacity of a compound to absorb moisture
• Absorbed moisture depends on environmental conditions
• Deliquescent substance absorbs moisture to a greater extent and liquefies itself
• Reason to study is that the moisture influence changes in chemical stability, flow and compressability
• After being stored at 25 °C/80 % humidity:
  • Slightly hygroscopic: weight increase from is greater/Equal to 0.2% but Less than 2% w/w -Hygroscopic: weight increase from Equals or Greater than 0.2% but Less than 15% w/w -Very hygroscopic: weight increase Greater than 15% w/w
• Flow-ability links with relative humidity

Controlling size

• Moisture levels are measures by TGA, Karl Fischer titration and Chromatography

Particle Size Affects Quality

• Dissolution, Solubility, Bioavailability, Content Uniformity influence quality parameters
• Improvement of solubility is possible by reducing the particle size
• Particle Size Determines Suspension
• instability results from too much reduction
• Content uniformity is risked by nonuniform particle size distribution
• Microscopy, Sedimentation, culter counter, nitrogen absorbation can determine particle size for suspensions
• Spherical drug are uniform
• Irregular particle shape is preferred for topical abrasive products

Density and Porosity

• Ratio of mass is substance to volume which depends greatly on particle size distribution and shape
• Determination is a problem
• Voids are classified as Interparticulate, intraparticulate, Open and Closed. Void volumes are classified for densities

Types of Density

• True density measures all space excluding molecule diamete
• Helium Pycnometer is used
• Bulk Density: Measures Total volume occupied by entire powder mass but is not original
• Graduated cylinders are measure the volume in militers
• Division of original weight shows Bulk Density
• Tapped Density: is determined by operated for the fixed number of taps
• constant volume is idea of tapped density

Size dosage

• Size dosage and type of form and is critical for Potency Drugs and Studied using Bulk and Tapped density
• Density is measured with a number of factors

Probelms To address density:

• Capsule formulation becomes too difficult
• low compressability is tablet difficult
• In Homogenity make it difficult to achieve formulation

Flow Properties

• Friction from flow property can be affected including frictional forces, surface tension forces, electric forces, and van der Waals forces.
• Parameter inclusion in preformulation is linked with hygro and particle size. flow is needed and is great when dose loading.

Flow Parameters

• As moisture uptake increases, flow detoriates on samples
• Irregular particle size is distrub normal rate

Humidity

• free flow 1 %= 0.30 percent Moisture Uptake
• low free flow 10% = 0.24 Moisture Uptake
• Less Freeze 20% = 0.27 percent Moisture Uptake
• Base of powder adheres (40% = 0.35 Percent Moisture Uptake )

Measurements

• solid drug substance can be measures with Hanser, carrs Repo etc.

Compressibility Index

• Compression= Tapped Density-Bulk/ Tapped *100 is Formula Example E3

Hs Ratio= Tapped / Bulk - Is Formula E4 Table used to correlate h index flow

Types of Static and dynamic

Static

• Fixed Cone/ Funnel methods Dynamic
• rotating- Tilting Bix

Excipients

• Give inadvertent or unintended effects
• Can effect therauptic
• Can Provide Justificaiton behind Inactive selective excipients
• Changes caused: - organoleptic properties
• Effects include dissolution- decrease potency, degrade toxity and physical effects

Generalities

• Drug Excipient May result in Change- Physical- Chemical

Compatibilitys

• Can result in formulation degradation- bond breakage

Hydro- oxidize/ Racemization and Mailler Reactions - This effects delitorious

Lactose with amino causes mailer reactions- bronchodilator cause reduction to ethylamine and lactose cause discoloration

Three way

• Action - excipient - Drug

Polymer - administered anti acidic - cause to resolve

• There are specific methods to provide side help with x-ray, chromatology help analysis and spectroscopy

Preformulation studies are essential in formulation design, focusing on the physical, chemical, and analytical properties of new chemical entities. These studies are multidisciplinary, involving pharmacology, toxicology, and chemistry. The goal is to administer the drug correctly, optimizing its availability and stability.