Intro to Oral Solids

  • How do we choose between so many choices of the same drug product?

    • Tune the release kinetics (input) to target a certain pharmacokinetic profile

      • Modify the release (input kinetics) to tailor the plasma concentration vs time profile (pharmacokinetics) for a specific effect

  • Kinetic barriers to drug absorption for oral solids

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

    • These kinetics processes directly influence the pharmacokinetics of a drug

    • Mainly concerned with

      • How quickly a pharmacological effect is initiated

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

  • Both solubility and  permeability affect tmax

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

  • Modifying the surface area term

    • 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 (particle size reduction) will not provide a significant improvement in bioavailability

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

  • Modifying the solubility term

    • Beginning with the "solid" in oral solids, there are a variety if forms or solids phases that may be selected for the active pharmaceutical ingredient (API)

    • Everything in a drug product is  deliberately included (from API to secondary packaging)

    • Selecting the appropriate solid form, main considerations are:

      • Solubility

      • Stability

      • Processability

  • Crystalline solids

    • Unique property of crystalline solids is periodicity

      • One building block (unit cell) may be repeated in space (3-dimensions) to create the entire solid

  • Polymorphism

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

    • Its not the chemical identity that's changing, 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 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 --> lattice needs to be broken apart

      • 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 solubility perspective, that means the more stable a polymorph, the more energy you have to put in to break the lattice apart

      • 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

      • 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 and cooled

      • Example of amorphous solid prepared via melt/cool method:

        • Glass (quartz sand heated to >3090F) and cooled

  • Amorphous solid dispersion

    • Role of the polymer

      • Stabilize the amorphous drug during storage

        • Prevents conversion back to crystal form

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

      • Enhance the drug dissolution rate during dissolution

        • Related 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 a BCS II or IV

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

  • Co-crystal

    • Been around for 100 years but only recently have demonstrated significant working potential

    • Co-crystal - a solid that is crystalline single-phase material composed of two or more different molecular ionic compounds in a stoichiometric ratio which is neither a solvate or simple salt WORKING DEFINITION

    • To be considered a co-crystal

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

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

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

    • Benefit of co-crystals is that even the most stable phase can still display a 1000x solubility advantage

    • Limitation is what co-former you choose

    • To improve 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

      • Heat of solvation may be affected too

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

  • Marketed co-crystal products

    • Lexapro

      • Escitalopram + oxalic acid

      • Approved: 2002

      • Indication: major depression and anxiety

    • Entresto

      • Sucabitril + valsartan

      • Approved: 2015

      • Indication: heart failure

    • Steglatro

      • Ertugliflozin + L-pyroglutamic acid

      • Approved: 2017

      • Indication: type 2 diabetes

  • Drug product quality control

    • A consistent theme in FPS is drug product design and ensuring the product manufactured is:

      • Stable - at least to the expiration date listed on the drug product

      • Accurately and precisely dosed

      • Identifiable - debossing, color coating, branding logo

      • Consistent in release profile - in vitro and in vivo

      • Tamper-resistant

    • To prove that a given drug product has achieved these goals, a list of product performance characteristics are defined and tested

    • Guidelines for testing are provided by the United States Pharmacopeia (USP)

  • Product performance characterization for oral solids

    • Appearance

    • Content uniformity

    • Disintegration and dissolution

    • Moisture content

    • Organic impurities

    • Capsule closure. - for hard capsule shells

    • Friability

    • Hardness

    • Packaging and storage

    • Testing is done using validated analytical methods to meet the drug product's specifications

    • A "validated" method provides documented evidence of suitability of a given application

  • Uniformity of dosage units

    • Weight variation (WV)

      • Used for most dosage units (tablet) with a dose of ≥ 25 mg API and ≥25% ratio of API weight to total drug product weight

    • Content uniformity (CU)

      • Assaying individual units using an appropriate analytical method

      • Used when a dosage unit doesn't qualify for the weight variation or when desired

    • Relative to WV, CU is a superior test because it provides an actual measure of drug content per dosage unit

  • Challenge of low-dose drug formulations

    • Synthroid is available in multiple different doses

    • Levothyroxine has a narrow therapeutic index

      • Patient is titrated to the right dosage amount

      • Need to have exceptional control on the manufacturing to ensure the patient is getting the right dose

  • Importance of compliance to tests

    • For establishing "uniformity of dosage units" the following critical elements must be demonstrated:

      • For each batch product, the mean content of API must lie between specified limit (typically 90-110% of label) throughout the shelf life of the product

      • There is a statistically defined limit to the spread in the individual content values of the tested dosage units

      • For products requiring USP uniformity of Dosage Units test, failure of this test means the batch of product cannot be legally solid in the US

  • Characterization tests

    • Tablet friability

    • Tablet breaking force

    • Disintegration time (tablet/capsule)

    • Dissolution

    • Loss on drying

    • Moisture sensitivity/uptake

  • Stability testing

    • Applied to all solid dosage forms, but there is no one specific test for stability because the requirements for each API are too specific

    • Intrinsic stability of the API is determined as a function of

      • Temperature

        • Thermal degradation

      • Humidity

        • Hydrolysis, crystallization

      • Light

        • Photodegradation, photo-oxidation

    • This is tested against different formulation components as well as different container/closure systems

      • Foil blister packaging

      • Amber bottle

    • Accelerated stability tests (stress testing) are performed on formulations in the proposed packaging to determine the appropriate storage conditions and estimate the product's shelf life

    • Most used guideline for stability testing is International Council for Harmonization (ICH) Guideline