part 4 flashcards of key bits besides stuff on ppt

Where are most drug molecules typically located towards the end of their manufacturing process?

Most drug molecules will be in solution, usually in organic solvents.

What occurs when the solvent evaporates during drug preparation?

Evaporation of the solvent leads to the precipitation of the drug as a solid. 

What are the two ways drug molecules can arrange themselves when forming a solid? 

They may arrange into a regular pattern (crystalline) or a random arrangement of molecules (amorphous).

How are drugs described if they can form more than one crystalline arrangement? 

polymorphic

Why does polymorphism create challenges in formulation science?

Different crystalline forms of a drug can exhibit different rates of dissolution, storage stability, and other properties.

What are the thermodynamic stability and batch uniformity advantages of crystalline solids? 

High Thermodynamic Stability: Resistant to moisture absorption and recrystallization during storage. 

Batch Uniformity: High purity, reproducible processing, and reliable mechanical flowability(how smoothly a power moves). 

Standardised Manufacturing: Straightforward compression for oral tablets and capsule filling.

What are the key limitations associated with crystalline drugs?

Low Aqueous Solubility: High lattice energy acts as an energy barrier to dissolution. 

Reduced Bioavailability: Suboptimal absorption rates. 

Risk of Polymorphism: Unintended conversion between different crystal forms during processing.

What are the key advantages of amorphous solid drug forms?

Apparent Solubility Boost: Lacks a rigid crystal lattice, enabling rapid hydration and dissolution. 

Enhanced Bioavailability: Dramatically increases systemic absorption of poorly water-soluble APIs. 

Faster Onset of Action: Ideal for therapeutic applications requiring rapid drug absorption. 

What are the primary limitations associated with amorphous drug forms?

Thermodynamic Instability: High free energy drives spontaneous recrystallization over time. (Low energy is usually preferred but this is high and messy)

Hygroscopic Sensitivity: Readily absorbs atmospheric moisture(acts like sponge, gets softer), lowering T_g and causing degradation. 

Complex Processing: Requires stabilizing polymer matrices (Amorphous Solid Dispersions). (As it’s so unstable, you have to lock it in a ASD to keep it stable)

Why might some drug molecules show poor aqueous solubility even in their optimal crystalline structure?

Due to factors such as high log P, tightly bound salt, etc

What are the 6 methods listed to deal with poor aqueous solubility and improve solubility? 

1. Choice of solvent used. 

2. Employing a cosolvent. 

3. Use of a different drug salt. 

4. Manipulation of pH of the solution. 

5. Complexation with cyclodextrins. 

6. Producing a different formulation type.

Why is water the most common solvent (2)

It’s polar nature

It’s biocompatibility

3 types of waters used in pharmaceuticals

Potable water(tap), purified water, water for injections BP

What is potable water - what can it be used for (2) and what may it contain?

Also known as tap water, it is suitable for drinking and useful in oral medicines, though it may contain mineral salts or other substances.

How is purified water prepared(3), and what precautions must be taken if it is stored before use? 

It is prepared by distillation, reverse osmosis, or deionisation of potable water. If stored before use, it must be freshly boiled and cooled to remove any microbial contamination.

How is Water for Injections BP produced, and what is its primary use?

It is produced by the sterilisation of pyrogen-free distilled water and is used in parenteral formulations.

When is water not a suitable solvent?

When drug is very lipophilic

Why are non-aqueous oral formulations relatively uncommon? (3)

Because many non-aqueous solvents taste unpleasant, may be toxic or irritant, and/or lack miscibility with physiological fluids. 

Where can non-aqueous formulations be useful?(2)

useful in parenteral (e.g., depot injections) or topical formulations (e.g., ointments).

How is a vehicle or base selected to ensure dissolution based on the "like dissolves like" principle?

The vehicle or base will be selected to match the drug's properties to ensure dissolution.

Examples of non-aq solvents

Alcohols, fixed vegetable oils, esters, dimethyl sulfoxide (DMSO)

Example of ester

Benzyl benzoate

Another job of non-aq solvents

Can be used alongside water as co solvent

How to use the cosolvent

Dissolve drug in more lipophilic solvent like alcohol and then the resulting solution is mixed with water

What precaution must be taken regarding drug concentration and the proportion of co-solvent used?

Care must be taken not to exceed the drug concentration or proportion of co-solvent used where the drug will precipitate (becomes solid)

What physical property must the non-aqueous solvent possess when used alongside water? 

The non-aqueous solvent used must be miscible with water

What issues can arise if a co-solvent is volatile(evaporates quickly)? 

Issues can arise if a co-solvent is volatile and evaporates from the solution.

What is the most commonly used cosolvent, and what drawback does it possess?

Ethanol is most commonly used, but it exerts a pharmacological effect which can negate its benefits. 

How can a clear product be made using phenobarbitone, which is virtually insoluble in water? 

By dissolving it in ethanol and then diluting with glycerol (an alcohol with three alcohol groups) and water.

How is propylene glycol (an alcohol with two alcohol groups per molecule) used with methyl hydroxybenzoate?

Methyl hydroxybenzoate is a preservative with poor water solubility used in oral medicines; a solution in propylene glycol can be added to formulations to ensure an adequate concentration is present(it helps it dissolve and hence be available)

What are Polyethylene Glycols (PEGs)

PEGs are long-chain polyethers that can be employed as cosolvents.

How are PEGs named, and how does the value of n affect their physical state? 

The name is based on the average chain length of the molecules present (n value). A chain length of \text{PEG}<400 is a liquid, while \text{PEG}>400 is a solid.

What is PEG 400, and why is it significant in liquid formulations? 

PEG 400 is a common excipient that is a slightly viscous liquid, and it is the longest PEG chain length that can be used as a liquid excipient.

Why can different PEGs be blended, and where are higher chain length PEGs used? 

Different PEGs can be blended to optimise properties (e.g., \text{PEG 200} + \text{PEG 400}). Higher chain length PEGs are used in solid and semi-solid formulations.

Why might a salt be needed if a pure drug is too lipophilic? 

A salt is needed to increase polarity and allow the drug to dissolve in water. 

What happens if a drug is too tightly bound to its counterion?

It is unlikely to be solvated and form a solution.

How does pH affect a drug in solution

It can affect the ionisation state of a drug if it has proton donor/acceptor moieties (groups). 

How may the pH of a solution be simply modulated + give examples(1), and how is the volume determined?(2)

By the addition of an acid (dilute {HCl}) or a base (dilute {NaOH}) as appropriate, with the volume determined either by calculation or use of a pH meter. 

What competing factors must be balanced when selecting acids or bases for a formulation? 

Care must be taken to balance the dilution of the formulation (using weak acids/bases) versus the risk of degradation of the drug or excipient (using strong acids/bases). 

What issue can still occur over time if pH manipulation is used, and what are its consequences? (2) and how to solve

The pH may still drift over time, which can lead to degradation or precipitation of the drug and/or excipients.

Add buffer

How do buffers handle any generation of acid or base within the formulation? Is there a limit?

Any generated acid or base (e.g., from chemical breakdown) will be counterbalanced by the buffer up to a certain point, known as the buffer capacity. 

How are pharmaceutical products designed regarding buffer capacity? 

Products are designed so that the buffer capacity is not exceeded during normal storage, transport, and use conditions.

What are the working pH ranges for Hydrochloric acid + sodium citrate and Borax + sodium hydroxide? 

Hydrochloric acid + sodium citrate: pH 1 - 5 

Borax + sodium hydroxide: pH 9.2 - 11

What are cyclodextrins in terms of their origin and structural shape?

They are semi-synthetic polysaccharides made up of glucose molecules bound together in a cyclic, "bottomless bucket" (or tube-like) structure. 

How many glucose units make up \alpha, \beta, and \gamma cyclodextrins, and what is the significance of these different sizes? 

6,7,8 - Different cavity sizes accommodate different sized drug molecules. 

Issues with cyclodextrin complexation

Drug may be hidden inside and can’t bind target

What type of complexes do cyclodextrins form?

Guest-host inclusion complexes

Under what conditions does cyclodextrin complexation work best? (2)

It works best when drug molecules possess a lipophilic moiety with the correct size to fit the cavity. 

How does inclusion complexation(drug is inside) alter the properties of the guest molecule, and what is the primary benefit? 

It greatly modifies the physical and chemical properties of the guest molecule, primarily by increasing aqueous solubility. 

What is required at the target membrane for a complexed drug to exert its effect, and why? 

It relies on dissociation at the target membrane because the bound drug is pharmacologically inactive.

What type of molecules can be employed in strategies similar to cyclodextrins to help solubilise poorly soluble drugs? 

Amphiphilic surfactant molecules. 

What specific structures are amphiphilic surfactant molecules able to form to help solubilise poorly soluble drugs? 

Micelles and liposomes.

What alternative formulation types may be more suitable when a solution is too difficult to achieve for a poorly soluble drug? 

Suspension/emulsion