3.2: Biopharmaceutics & Formulation Science

3.2: Biopharmaceutics & Formulation Science

Dosage Forms and Drug Delivery Systems

Pharmaceutical dosage forms are complex systems designed to deliver the active pharmaceutical ingredient (API) safely, effectively, and reproducibly to the target site of action. The design of these systems significantly influences drug release, absorption kinetics, and patient compliance.

Oral Dosage Forms: Immediate vs. Modified Release

Oral drug delivery remains the most common route of administration. Modified-release (MR) formulations are engineered to alter the rate or site of drug release.

• Enteric-Coated (EC) Formulations: These utilize pH-sensitive polymers (e.g., cellulose acetate phthalate, methacrylic acid copolymers) that remain insoluble in the acidic stomach (pH 1–3) but dissolve in the neutral-to-alkaline duodenum (pH > 5.5). Enteric coating is used to protect the stomach from irritating APIs (e.g., aspirin, NSAIDs) or to protect acid-labile drugs (e.g., proton pump inhibitors like omeprazole) from gastric degradation. EC tablets must never be crushed or chewed, as this destroys the protective polymer layer.
• Extended-Release (ER/SR/CR) Formulations: These control the rate of drug release over an extended period. Mechanisms include hydrophilic matrix systems (e.g., hypromellose), which swell upon contact with GI fluid to form a gel barrier through which the drug slowly diffuses, or osmotic pump systems (e.g., OROS technology used in nifedipine controlled-release).
• Clinical Danger (Dose Dumping): Modified-release systems can be susceptible to "dose dumping" in the presence of alcohol (ethanol). Ethanol can dissolve certain rate-controlling polymeric membranes or matrices, causing the rapid, uncontrolled release of the entire dose, which can lead to fatal toxicity (particularly with potent opioids like hydromorphone or morphine ER).

Parenteral Formulations and Depot Preparations

Parenteral routes bypass the gastrointestinal tract and first-pass hepatic metabolism.

• Intravenous (IV): Provides immediate systemic availability and 100% bioavailability. Solutions must be completely free of particulate matter. Emulsions (e.g., propofol) can be given IV, but suspensions must never be administered intravenously due to the risk of pulmonary capillary embolism.
• Subcutaneous (SC) and Intramuscular (IM): Absorption is governed by local blood flow and formulation type. SC and IM depots are formulated as oil-based solutions (e.g., flupentixol decanoate in coconut oil) or microcrystalline suspensions (e.g., medroxyprogesterone acetate). These release the drug slowly over weeks or months.

Transdermal Drug Delivery Systems (TDDS)

Transdermal patches deliver drugs systemically across the stratum corneum.

• Matrix Patches: The API is homogeneously dispersed within a polymeric adhesive matrix. The rate of release is controlled by the matrix itself or the skin. Matrix patches can technically be cut to adjust the dose if the drug is uniformly distributed (though clinical guidelines generally discourage cutting unless specifically supported by the manufacturer, such as with certain lidocaine patches).
• Reservoir Patches: Contain a liquid or gel drug reservoir separated from the skin by a rate-controlling semipermeable membrane. Reservoir patches must never be cut. Cutting a reservoir patch causes immediate leakage of the drug gel, resulting in rapid systemic absorption of the entire dose ("dose dumping") and potential toxicity (e.g., fentanyl overdose).
• Clinical Practice Alert (Heat Effects): Application of external heat (e.g., electric blankets, saunas, hot baths, or high body temperature from fever) increases skin blood flow and drug diffusion rates through the stratum corneum, dramatically increasing systemic absorption of transdermal drugs (especially transdermal fentanyl), which can lead to life-threatening respiratory depression.

Inhalation Formulations

Inhalation delivers drugs directly to the airways for local action (e.g., salbutamol, fluticasone) or systemic absorption.

• Particle Size and Deposition: The site of aerosol deposition is determined by aerodynamic particle size:
  • > 10 µm: Deposited in the mouth and oropharynx (causing local side effects like oral thrush with inhaled corticosteroids).
  • 1 to 5 µm (Respirable fraction): Reaches the bronchioles and alveolar spaces (ideal for asthma and COPD therapy).
  • < 1 µm: Behaves as a colloid and is largely exhaled without deposition.
• Devices: Pressurised metered-dose inhalers (pMDIs) require hand-breath coordination unless used with a spacer. Spacers slow down particle velocity and allow large particles to deposit on the spacer walls rather than the oropharynx, reducing systemic side effects and improving lung deposition. Dry powder inhalers (DPIs) are breath-actuated but require a minimum inspiratory flow rate (e.g., 30–60 L/min) to de-aggregate the powder.

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Excipients and Their Functions in Formulations

Excipients are pharmacologically inactive substances added to a formulation to facilitate manufacture, protect the API, enhance solubility, or control drug release.

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Osmolarity, Osmolality, and Tonicity

Understanding osmotic properties is critical when formulating or preparing parenteral, ophthalmic, and nasal preparations.

• Osmolarity: The number of osmoles of solute per litre of solution (Osm/L or mOsm/L).
• Osmolality: The number of osmoles of solute per kilogram of solvent (Osm/kg or mOsm/kg). Osmolality is temperature-independent and preferred in clinical laboratory settings.
• Tonicity: A biological term describing the osmotic pressure gradient between two solutions separated by a semipermeable membrane (e.g., red blood cell membrane).
  • Isotonic: Solutions with the same osmotic pressure as body fluids (~280–300 mOsm/L).
  • Hypertonic: Osmolarity > 350 mOsm/L. Causes cell shrinkage (crenation) due to water efflux.
  • Hypotonic: Osmolarity < 250 mOsm/L. Causes cell swelling and lysis (hemolysis of red blood cells) due to water influx. Intravenous infusions of highly hypotonic solutions (e.g., sterile water for injection alone) are extremely dangerous and can cause fatal hemolysis.

Tonicity Adjustment Calculations (Sodium Chloride Equivalent Method)

The Sodium Chloride Equivalent ($E$) of a drug is the mass of sodium chloride (in grams) that produces the same osmotic effect as 1 gram of the drug.

$\text{Mass of NaCl represented by drug} = \text{Mass of drug (g)} \times E$

To make a solution volume $V$ (in mL) isotonic (equivalent to 0.9% w/v NaCl): $\text{Total NaCl required for isotonicity} = 0.009 \times V$ $\text{NaCl to be added} = (0.009 \times V) - (\text{Mass of drug (g)} \times E)$

Worked Example:

Calculate the amount of sodium chloride needed to make 50 mL of a 2% w/v solution of Drug X ($E = 0.20$) isotonic with blood.

1. Calculate the mass of Drug X in the solution: $\text{Mass of Drug X} = \frac{2\text{ g}}{100\text{ mL}} \times 50\text{ mL} = 1.0\text{ g}$
2. Calculate the NaCl equivalent of the drug: $\text{NaCl equivalent} = 1.0\text{ g} \times 0.20 = 0.20\text{ g of NaCl}$
3. Calculate the total mass of NaCl needed for an isotonic 50 mL solution: $\text{Total NaCl needed} = 50\text{ mL} \times 0.009\text{ g/mL} = 0.45\text{ g}$
4. Calculate the amount of NaCl to add: $\text{NaCl to add} = 0.45\text{ g} - 0.20\text{ g} = 0.25\text{ g}$ Therefore, 0.25 g of sodium chloride must be added to the solution.