Solid Dosage Formulations

Topic 2 - Design of Solid Dosage Formulations

• This topic is based on content from Chemical Engineering in the Pharmaceutical Industry, 2nd edition, Chapter 2, Wiley, 2019, edited by M. T. am Ende & D. J. am Ende.

Dosage Forms: Definition

• Dosage forms are the method by which drug molecules are delivered to the body.

The Need for Dosage Forms

• Dosage forms are needed for:
• Accurate dosing
• Protection using coated tablets and sealed ampules
• Protection from gastric juice
• Masking taste and odor
• Placement of drugs into body tissues
• Optimal drug action
• Sustained release
• Controlled release
• Insertion into body cavities, such as rectally or vaginally
• Use of a desired vehicle for insoluble drugs

Types of Dosage Forms

• Dosage forms are classified according to their route of administration and physical form.
• Route of administration includes oral, topical, rectal, parenteral, vaginal, inhaled, ophthalmic, and otic.
• Physical form includes solid, semisolid, liquid, and gaseous.

Oral Route

• The oral route is the most common way to administer drugs.
• The oral route is convenient for self-administration and is a safe way of drug administration
• Manufacturing the the oral route is more profitable than parenteral dosage forms because parenterals require trained personnel.
• Over 80% of drugs made with systematic effects are marketed as oral dosage forms
• Tablets are the most common among oral dosage forms due to low manufacturing costs, increased stability and virtual tamper resistance.

Types of Solid Oral Dosage Forms and Characteristics

• Immediate release tablets: disintegrate in the stomach after being taken orally.
• Delayed release tablets: enteric-coated to remain intact in the stomach and disintegrate in the intestine for absorption.
• Sustained/controlled release tablets: release the drug slowly to decrease frequency of administration.
• Chewable tablets: tablets that are broken by chewing before swallowing with water.
• Orally disintegrating tablets: disintegrate in oral cavity without water to form a suspension for swallowing.
• Hard gelatin capsules: two-piece capsule shells filled with granules, powders, pellets, sprinkles, semisolids, and oils.
• Soft gelatin capsules: one-piece capsules filled with oily liquid.
• Sachets: single-dose unit bags containing granules.

Steps of Drug Delivery to the Systemic Circulation

• Steps include oral administration of tablets, initial transport of the drug through the gastrointestinal membrane, dissolution of the drug in GI fluids, and drug absorption from the GI tract.
• For the drug to be brought into solution in the GI fluids, it should be capable of crossing the intestinal membrane into the systemic circulation
• The rate of dissolution of the drug in the GI lumen can be a rate-limiting step in the absorption of drugs given orally.

Fate of Solid Dosage Form Following Oral Administration

• The slowest of either dissolution or absorption determines the rate of availability of the drug from tablet formulation.

Drug Bioavailability

• Bioavailability is the extent and rate at which a drug enters systemic circulation, accessing the site of action.
• Factors affecting bioavailability include physical, chemical, biopharmaceutical properties, and tablet design/production.
• Tablet formulation design has moved from an art to a well-defined science.

Good Formulation and TPP

• A good formulation is bioavailable, manufacturable, chemically/physically stable, and meets quality/safety standards.
• Formulation goals are described as the target product profile (TPP).
• TPP summarizes features that, if achieved, provide drug efficacy, patient compliance, and marketability.

Typical Target Product Profile (TPP) for an Immediate Release (IR) Tablet

• TPP for an immediate release tablet considers what to examine from other similar products, improvements, dosages, populations, etc

Physicochemical Properties, Solubility and Drug Dissolution

• Integrating the physicochemical, mechanical, and biopharmaceutical properties of drug substances is essential for developing an effective drug product.
• Properties include solubility/drug dissolution, partition coefficient, crystal properties, particle size, bulk powder properties, and melting point/hygroscopicity.
• Aqueous solubility dictates the amount of compound that dissolves for absorption.
• Low aqueous solubility could be subject to dissolution rate-limited absorption in the GI residence time.
• Dissolution is the dynamic process of a material dissolving in a solvent, characterized by a rate.
• Solubility is the amount of material dissolved per unit volume of solvent, characterized as a concentration.
• Solubility is used as a short term for saturation solubility, and can be used to describe the maximum amount of drug dissolved at maximum conditions
• Intrinsic solubility describes the solubility of the neutral form of an ionizable drug

Dissolution Rates

• Dissolution rates is proportional to aqueous solubility, "Cs", and the "A" surface area exposed to the dissolution medium
• When developing an immediate release dosage form of poorly soluble drugs it is key to increase drug-dissolution rates by increasing the surface area by reducing particle sizes

Noyes-Whitney Equation

• This equation describes the dissolution rate of a solute from a solution: dC/dt = (D x A)/h x (Cs - Ct)
• "D" is the diffusion coefficient of the drug substance
• "A" is the drug particle surface area
• “Cs" is the saturation solubility
• "Ct" is the drug concentration in the bulk solution at a given time

Dissolution Rates, Dissolution Studies

• The dissolution rate, rather than the saturated solublity, is the primary determinant in the absorption process of a sparingly low soluble drug
• Dissolution rate studies may include evaluating the different solid forms ( e.g. salts, solvates, polymorphs, amorphous, and stereoisomers) or different particle sizes of a drug
• The dissolution rate can be determined for a constant surface area using a rotating disc apparatus or for a dispersed powder using a beaker with agitation

Partition Coefficient

• Partition coefficient is the relationship between chemical structure, lipophilicity, and its disposition in vivo.
• Lipophilicity is described in terms of a partition coefficient, log P
• The partition coefficient is the ratio of the concentration of the unionized compound at equilibrium between organic and aqueous phases

Log P Formula

• logP = [A]organic / [A]aqueous where [A] = concentration
• For ionizable drugs, the ionized species does not partition into any organic phase.
• The apparent partition coefficient, D, is calculated from:
  • Acids : logD = logP-log [1+10(pH-pKa)]
  • Bases : logD = logP-log [1 + 10(pKa-pH)]
• pKa is the dissociation constant.
• The lipid phase in pharmaceutical studies uses the octanol/water system
• Good passive absorption occurs when Compounds have log P values between 3 and 6
• Poor passive transport occurs when log P values are less than 3 or greater than 6

Crystal Properties

• Crystal Properties & Polymorphism includes the idea that Most drug substances appear in more than one polymorphic form.
• Polymorphs differ in molecular packing (crystal structure), but share the same chemical composition.
• Polymorphs have implications on formulation development and biopharmaceutical properties
• Fishbone Schematic of Physical Property Differences among Polymorphs will display differences in mechanical electrical and thermal conductivity

Crystal Properties and Polymorphism, Formulating Perspective

• Metastable polymorphs tend to convert to thermodynamically more table forms over time, which can cause lower quality drugs
• The thermodynamically stable form of the API is favored, but biopharmaceutical and processability factors may influence choosing metastable forms
• Even when a stable form is chosen, Polymorphic form conversion may still occur
• Polymorphic transformations occur during pharmaceutical processing such as compaction and compression
• Seven crystal system categories are cubic, monoclinic, triclinic, hexagonal, trigonal, orthorhombic, and tetragonal

Crystal Systems

• The angles and side properties of crystals vary with the different crystal systems (simple cubic, tetragonal, orthorhombic, rhombohedral, monoclinic, triclinic and hexagonal)

Particle Size, Particle Morphology, and Surface Area

• Affects the drug in terms of Drug/API size, Drug/API shape, Drug/API and Drug/API surface morphology
• Dissolution and Chemical Reactivity are affected by Bulk flow, Compactability, Formulation homogeneity, and Surface-area

Particle Size and Flow Properties

• Spherical particles have the least contact surface area with good flow
• Acicular particles have lower flow
• Milling of long acicular crystals enhance flow
• Excessively small particles are cohesive and aggravate the flow

Particle Size

• Crystal shape impacts the effect of mixing and tabletability
• Plate-shaped crystals result in greater tabletability than prism-shaped crystals.
• Paracetamol particle size and shape will impact compressibility with binary mixtures
• Compressibility is increased with particle size and irregular crystals
• Compactibility is increased with a decrease in particle size

Particle Size and Drug Content Uniformity

• Particle size affects drug content uniformity (CU).
• Direct compression (DC) formulations need to have a drug particle size small enough to meet US Pharmacopeia (USP) requirements on CU
• Low-dose blends with larger drug sizes aren't able to meet the specifications of the USP standards
• Smaller particles pass the USP standards

Surface Areas of Drug Particles

• Surface area of drug particles are important for dissolution
• Particle size reduction micronization is often utilized to increase the surface area and enhance dissolution rates of drugs
• Micronization enhanced the bioavailability of felodipine when formed as extended release tablets

###Methods to Determining Particle Size

• Light microscopy
• SEM
• Sieve analysis
• Various electronic sensing-zone particle counters
• Available for surface area measurement by air permeability or various gas absorption techniques.

Bulk Powder Properties

• Desnity and Porosity are two pharmaceutical properties using particle size, shape and surface area

Porosity Formulas

• The formulas are:
  • Interparticle porosity = 1- (Bulk Density/Apparent particle density)
  • Intrapaticle porosity = 1 - (Apparent particle density/ True particle density)
  • Total Porosity = 1- (Bulk density/True Particle density)
• Tapped and bulk density help determine compressibility index and hausner ratios, which measure propensity for powder to be to flow when compressed

Thumb for Flow

• Compressibility index above 30% indicates poor flow
• Hausner ratio varies from 1.2 for free flow to 1.6 for cohesive flow

Calculations

• Hausner Ratio = Tapped density/ Bulk density
• Compressibility Carr Index - ((Tapped - Bulk) density/Bulk density) *100

Flow Character and Hausner Ratio

• Compressibility index ranges from percent to ratios
• Flow character may vary from excellant, good, fair, passable, poor, very poor or vey very poor in accorcance with hausner ration

Low Melting Point

• Materials that melt at low temperatures tend to less manufacturerable or able to be handled in conventional solid forms
• Melting points must have above 60 degrees celcius, or the formulation gets problematic
• Temperatures in the devices can exceed above 50 degrees
• Hot spots on milling may have higher temperatures

Hygroscopicity and Formulation

• Moisture uptake can affect properties related to water properties like flow, stability and compactibility
• Type of moisture is critical to understanding and knowing the impact of deformation

Biological Property

• The study relationship between dosages, forms, routes and administration on the rate of absorption
• Oral absorption occurs when the coefficent is high and there's maximum solubility at the site of absorption that results in a Pharmological response the properties

Pharmocutical Properties

• A goal is to have a Rational dosage and an undersranding factors of tract properties

###Formulations and Oral Bioavailability is Depending to these Factors

• Soluibility, permeability and stability are all factors of this
• abosorbialty factor also depends on soubility and permeability

Drugs and Classifications

• Divided into four classification with solubility and permeability properties

Mechanical Properties and Material

• Material plays a big role in manufactured drugs
• Properties of perticles and affect unit of operation related to compressions, milling and granulation
• Mechanical properties of drugs need to be quantified
• Excipients and Drug properties

Types of Character

• Like materials that have Elastic, Plastici, Viscoelastic, Hard, Tough, Brittile

tools to identify materials

• Tensile strenght
• Compressive strenght
• Shear strength

Mechanical Property and Characterization

• Used in for Static testing is from 1-100 g
• Used from for dynamic testing is from is from 2-10 g
• Static dissection help study many mechanical propreties
• Hard to find production scales is one limit

Static Tester

• Tensile strengh
• Hardness
• Young Modulus
• Tableting Index

Dynamic Tester

• force and display profiles
• volume
• aplied pressure profile
• Check elquation