Preformulation in Pharmaceuticals

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

Which factor is NOT a reason for polymorphism in crystals?

Molecular weight (correct)

Level of supersaturation

Temperature

Solvent differences

What characteristic is primarily associated with the stable β form of Theobroma oil used in suppositories?

Melting point of 22 °C

Melting point of 28 °C (correct)

Melting point of 18 °C

Melting point of 34.5 °C

How does the internal structure of a crystal influence its properties?

It does not influence bulk properties.

It affects only the solubility.

It affects only the melting point.

It can alter both the crystal habit and bulk properties. (correct)

What is the main difference in absorption between amorphous and crystalline forms of a drug?

Amorphous forms are absorbed more rapidly. Signup and view all the answers

What is a characteristic of pseudopolymorphs?

They include co-crystals of materials with trapped solvent. Signup and view all the answers

In the context of thermal analysis, what does TGA primarily monitor during preformulation studies?

Desolvation and decomposition processes Signup and view all the answers

What effect does overheating have on the polymorphic behavior of Theobroma oil?

It may lead to the formation of other polymorphs upon cooling Signup and view all the answers

Which statement is true about the relationship between crystalline form and drug activity in insulin?

Insulin activity can vary with its crystalline form influenced by pH. Signup and view all the answers

What is the primary objective of preformulation studies?

To establish the physicochemical parameters for drug development Signup and view all the answers

Which of the following is NOT a goal of preformulation?

To develop a marketing strategy for the drug Signup and view all the answers

Which type of properties are investigated in preformulation studies?

Physical and chemical properties Signup and view all the answers

What is the significance of establishing the physical description of a drug substance in preformulation?

It informs the dosage form development process Signup and view all the answers

Pharmaceutical excipients are used for which of the following purposes?

To enhance solubility and stability of drug formulations Signup and view all the answers

What role does compatibility with excipients play in preformulation studies?

It impacts the processing and storage conditions of the drug Signup and view all the answers

Why is it important to analyze both solid and liquid forms of drugs in preformulation studies?

To understand their physicochemical properties relevant to dosage form design Signup and view all the answers

Which of the following aspects is NOT typically analyzed during preformulation studies?

Therapeutic mechanisms of action Signup and view all the answers

What primarily influences the proportion of un-ionized form of a drug in a given environment?

Environmental pH and drug’s pKa Signup and view all the answers

In which pH environment is a weak acid with a pKa of 4.4 predominately un-ionized?

pH 1.4 Signup and view all the answers

Given two drugs with pKa values of 2 and 6 respectively, which environment would favor the absorption of the drug with pKa 2?

Stomach (pH 2) Signup and view all the answers

What best describes the stability analysis in relation to drug formulation?

It evaluates drug excipient compatibility. Signup and view all the answers

What does a partition coefficient measure in the context of drug absorption?

The distribution of un-ionized drug between organic and aqueous phases Signup and view all the answers

What principle underlies cascade impaction?

A particle will hit a surface if its inertia overcomes the drug force. Signup and view all the answers

Which method measures particle size using light diffraction?

Light energy diffraction Signup and view all the answers

How does particle shape affect pharmaceutical formulations?

It influences packing, flow, and compaction properties. Signup and view all the answers

What is the relationship between particle size and surface area?

Smaller particle size results in greater surface area. Signup and view all the answers

Which temperature is NOT typically used to measure intrinsic solubility?

25 °C as a standard Signup and view all the answers

What signifies a saturated solution in solubility studies?

The maximum amount of solute has dissolved in equilibrium. Signup and view all the answers

What is a major factor in using laser holography for particle size measurement?

It allows for individual imaging and sizing of particles. Signup and view all the answers

In the context of cascade impaction, what primarily determines whether a particle impacts a surface?

The combined inertia of the particle and drug force. Signup and view all the answers

What is the significance of a solubility measurement of less than 1 mg/ml for a drug?

It suggests the need for a salt, especially for tablet or capsule formulations. Signup and view all the answers

Which of the following counter-ions is NOT accepted for basic drugs?

Magnesium Signup and view all the answers

What is the expected solubility comparison between a basic drug and its hydrochloride salt?

The hydrochloride salt is expected to have significantly higher solubility than the basic drug. Signup and view all the answers

Which statement regarding salt formation is incorrect?

Salts prepared from strong acids are usually poorly soluble. Signup and view all the answers

What might happen if a drug's salt is formed using a hydrochloric acid salt in aerosol packaging?

It may lead to product instability. Signup and view all the answers

In terms of physicochemical properties, how do different salts of a drug typically affect its pharmacology?

Different salts do not typically change pharmacology, only physical properties. Signup and view all the answers

What pH range is ideal for injections to prevent vessel damage?

3-9 Signup and view all the answers

What is the primary purpose of determining pKa in drug formulation?

To understand the ionization state of the drug related to pH. Signup and view all the answers

Study Notes

Preformulation

Preformulation utilizes biopharmaceutical principles to determine the physicochemical properties of a drug substance.
The goal is to develop safe, effective, and stable dosage forms.
This stage begins when a new drug shows promise in animal models.

Objectives of Preformulation

Generate information to design an optimal drug delivery system.
Establish physicochemical parameters of new drug substances.
Determine kinetic rate profiles.
Establish physical characteristics.
Establish compatibility with common excipients.
Choose the correct form of the drug substance.
Provide insights into processing and storage to ensure quality.

Pharmaceutical Excipients

Formulation additives that aid in:
- Solubilization
- Suspension
- Thickening
- Preservation
- Emulsification
- Dissolution modification
- Compressibility improvement
- Flavoring
- Sweetening

Physical Description

It is important to understand the physical description of a drug substance, whether it is solid, semisolid, or liquid.
Most drugs are solid materials, with a smaller number being liquids.

Bulk Characterization

Crystallinity:
- Crystal habit describes the outer appearance of a crystal.
- Internal structure refers to the molecular arrangement within the solid.
- Changes in internal structure often alter crystal habit.

Polymorphism

Polymorphism: More than one shape.
Causes:
- Solvent differences
- Impurities
- Supersaturation levels
- Temperature
- Pressure

Polymorphism: Effects on Pharmaceutical Formulations

Theobroma Oil (Cocoa Butter)
- Used in suppositories, has 4 polymorphs.
- The stable beta form is used in suppositories.
- Overheating can cause the formation of other polymorphs upon solidifying.
Insulin:
- Different crystalline forms can lead to different activity.
- In the presence of acetate buffer, zinc combines with insulin to form a crystalline or amorphous complex.
- Amorphous insulin is absorbed rapidly with a short half-life.
- Crystalline insulin is absorbed slowly with a long duration of action.

Pseudopolymorphs: Solvates

Co-crystals of a material with trapped solvent.
Formed during crystallization from organic solvents.
Can transition to “unsolvated” forms over time.

Analytical Methods for Characterizing Solid Forms

Microscopy
Hot Stage Microscopy
Thermal Analysis:
- Differential Scanning Calorimetry (DSC)
- Thermogravimetric Analysis (TGA)

Thermal Analysis Applications

Monitoring desolvation and decomposition processes
Determining melting points, glass transition temperatures, and enthalpy changes.

Particle Size Determination Methods

Sieving:
- Separating particles based on size using a sieve.
Microscopy:
- Viewing particles under a microscope to measure their dimensions.
Cascade Impaction:
- Particles are driven by an airstream and impact a surface, providing information about size and size distribution.
Light Energy Diffraction:
- Particle size is determined by reducing the amount of light reaching a sensor as particles pass through.
Laser Holography:
- A pulsed laser is fired through an aerosolized particle spray and photographed in three dimensions.

Powder Flow Properties

Angle of Repose:
- Measured by allowing a powder to flow from a funnel onto a flat surface.
- A higher angle of repose indicates poorer flowability.
Carr's Index and Hausner Ratio:
- Ratios based on tapped density and bulk density measurements.
- Used to assess flowability and compressibility.

Particle Shape

Affects surface area, flow, packing, and compaction properties.
Spheres have the minimum surface area per unit volume.

Surface Area

Particle size and surface area are inversely related.
Smaller particles have a larger surface area.

Solubility Studies

Dissolution: The transfer of molecules or ions from a solid state to a solution.
Solubility: The amount of a substance that dissolves in a solvent when equilibrium is reached.
Intrinsic solubility (Co):
- The solubility value obtained in acid for a weak acid or in base for a weak base.
- Represents the fundamental solubility when completely unionized.
- Important for predicting drug absorption and bioavailability.

Drug Salts

A solubility of less than 1 mg/ml may require the formation of a salt, particularly for tablet or capsule formulations.
Acceptable Counter-ions:
- Basic drugs: Hydrochloride, sulfate, maleate, phosphate, salicylate, lactate, citrate, tartarate, acetate.
- Acidic drugs: Sodium, potassium, lithium, calcium, magnesium, zinc.

Salt Formation

Involves an acid (A), a base (B), and solvents.
A proton (H+) is transferred from the acid to the base.
The majority of drugs are basic (B), so suitable acidic counter-ions are chosen.
The goal is to select the most crystalline salt form.

Salt Formation Considerations

Salts from strong acids or bases are highly soluble but hygroscopic.
Injections should have a pH of 3-9 to prevent vessel damage and pain.
Oral syrups should not be too acidic for palatability.

pKa Determination

The pH at which the concentrations of ionized and unionized forms of a drug are equal.
Determines the proportion of un-ionized form present, which influences membrane permeability.
Lower pH than pKa favors the un-ionized form of weak acids and the ionized form of weak bases.
Higher pH than pKa favors the ionized form of weak acids and the un-ionized form of weak bases.

Partition Coefficient

The ratio of unionized drug distributed between organic and aqueous phases at equilibrium.
Helps predict drug distribution between different compartments of the body (e.g., blood, tissues, and organs).
A higher partition coefficient indicates greater lipophilicity, which can affect absorption, permeation, distribution, and elimination.

Stability Analysis

Chemical Stability: Assessing the degradation of the drug over time due to chemical reactions.
Physical Stability: Assessing changes in physical properties like crystal form, particle size, and appearance.
Stability studies:
- Accelerated stability: Assessing stability under extremes of temperature or humidity.
- Long-term stability: Assessing stability under realistic storage conditions.

Drug Excipient Compatibility

Investigating potential interactions between the drug and excipients.
Interactions can lead to changes in drug stability, dissolution, bioavailability, or physical appearance.
Methods for Excipient Compatibility Studies:
- Spectroscopic analysis (e.g., IR, Raman, UV-Vis)
- Thermal analysis (e.g., DSC, TGA)
- Microscopy
It's crucial to ensure that excipients are compatible with the drug substance to maintain the quality and safety of the dosage form.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz focuses on the principles and objectives of preformulation in drug development. It covers the physicochemical properties of drug substances, the role of pharmaceutical excipients, and the importance of establishing optimal drug delivery systems. Test your knowledge on key concepts and applications in this critical stage of pharmaceutical formulation.