Nanosuspensions for Improved Drug Delivery: A Review of Preparation Methods and Applications.

Oral liquid medications are vital pharmaceutical formulations, making up about 90% of the global drug market and offering numerous benefits for patient care and convenience.

Key Facts and Advantages of Oral Liquids

Oral liquid dosage forms (like solutions, syrups, and suspensions) are widely preferred for several reasons:

• Ease of Administration: They are ideal for patients who have difficulty swallowing tablets or capsules, such as children (pediatric), the elderly (geriatric), and patients with swallowing disorders (dysphagia).
• Rapid Absorption and Bioavailability: Since the active drug is already dissolved or highly dispersed, liquids often have an improved dissolution rate and faster absorption, which enhances the drug's effectiveness (bioavailability), particularly for drugs that are poorly soluble as solids.
• High Compliance: Patient adherence is generally higher with oral liquids than with injections or inhalers.
• Palatability: The liquid medium can be easily modified with sweeteners and flavoring to mask unpleasant tastes and boost patient compliance.
• Targeting: Drugs administered orally can be formulated to specifically target regions of the GI tract for localized treatment of conditions like ulcers, inflammation, and certain cancers.
• Market Dominance: Oral formulations are the most common and cost-effective method of drug delivery, accounting for roughly $35 billion in value among top-selling products.

Fig 1.ORAL DOSAGE FORM

Classification and Formulation Challenges

Oral liquids are primarily classified by their composition:

• Monophasic Liquids: Contain only one phase (e.g., syrups, elixirs).
• Biphasic Liquids: Contain two distinct phases (e.g., suspensions, emulsions).

The Challenge of Poor Solubility

A major hurdle in drug development is that over 40% of new drug candidates are poorly soluble in water. Formulating these drugs is complex, as many conventional methods (like salt formation, using co-solvents, or micronization) are not universally effective.

Nanotechnology Solution

To overcome solubility and absorption issues (especially for drugs classified as BCS Class II or IV), pharmaceutical scientists are turning to nanotechnology.

• Nanosuspensions, which involve reducing drug particles to the nanometer size, are a promising approach. This technique is particularly effective for highly lipophilic drugs (high) or those insoluble in both aqueous and organic solvents, offering a way to significantly enhance solubility and facilitate absorption across the GI barrier.

Fig 2: NANOSUSPENSION DOSAGE FORM

CLASSIFICATION:

Fig 3: CLASSIFICATION OF LIQUID DOSAGE FORM

IDEAL PROPERTIES:

A high-quality oral liquid formulation must satisfy strict criteria across four main areas: stability, patient acceptance, ease of use, and therapeutic efficacy.

1. Robust Stability and Integrity

The liquid must maintain its quality and potency over time.

• Chemical Integrity: The Active Pharmaceutical Ingredient (API) must not degrade. This requires the liquid's pH to be precisely maintained at the level that ensures maximum drug stability.
• Physical Uniformity (Homogeneity):
  • Solutions/Syrups must remain clear without any sign of settled material or cloudiness.
  • Suspensions must settle slowly, and any sediment formed must be easily and fully re-dispersed with simple shaking (no caking).
  • Emulsions must remain as a single well-mixed unit, resisting phase separation (like creaming or cracking).
• Microbial Resistance: The product must be protected from contamination and growth of bacteria, yeast, and mold, typically through the incorporation of effective preservatives.

2. High Patient Acceptance (Organoleptic Quality)

The medication must be palatable to ensure patients, especially vulnerable groups like children and the elderly, complete their treatment.

• Palatability: The taste must be acceptable or pleasant. Formulators must successfully mask any bitter or unpleasant flavors from the drug using appropriate sweeteners and flavorings.
• Visual Appeal: The liquid should possess an attractive, uniform color and an overall pleasant appearance.
• Odor: The scent must be acceptable and complementary to the chosen flavor.

3. Ease of Administration and Accurate Dosing

The product must be convenient and reliable for daily use.

• Swallowability: The liquid's thickness (viscosity) must be easy to pour and effortless to swallow, making it suitable for patients who have trouble with pills.
• Dosing Accuracy: The formulation must allow for the precise and reproducible measurement of a dose using the provided dispensing device (e.g., dropper or syringe).
• Pourability: The viscosity should be optimized—thick enough for stability (e.g., to prevent suspension particles from settling too quickly), but fluid enough to pour easily from the bottle without being excessively sticky.

4. Optimal Biopharmaceutical Performance

The medicine must deliver the drug effectively for the intended therapeutic action.

• Bioavailability: The drug should be quickly and predictably available for absorption into the bloodstream. Liquids generally offer a faster onset of action than solid forms.
• Safety and Tolerance: The formulation must be non-toxic, non-irritating, and non-sensitizing to the patient's tissues.
• Component Compatibility: All inactive ingredients (excipients) must be chemically inert and perfectly compatible with the active drug and the container to prevent unexpected reactions or degradation.
• RATIONALE

A. Addressing Formulation and Stability Challenges

• For Insoluble Drugs: Suspensions are the only viable liquid option when a drug is insoluble or poorly soluble in common pharmaceutical solvents (like water). The drug is dispersed as solid particles instead of being dissolved.
• To Improve Chemical Stability: Many drugs degrade quickly when fully dissolved in water. By keeping the drug in its solid, undissolved state (often as a dry powder reconstituted just before use), suspensions protect the drug from chemical breakdown, significantly increasing its shelf-life.

B. Enhancing Patient Experience and Functionality

• To Mask Unpleasant Taste: Making the drug into an insoluble suspension is an effective way to mask bitter or objectionable tastes. The drug particles interact less with taste buds, improving the palatability, especially for pediatric patients.
• For Ease of Administration: Suspensions are a necessary liquid alternative for patients (children, the elderly, or those with swallowing difficulties) who cannot take solid dosage forms like tablets or capsules.
• To Control Action: They can be designed to provide sustained or prolonged action (depot effect), particularly in injectable forms, as the particles slowly dissolve in the body over time.
• To Enhance Bioavailability (over Solids): Because the drug is already delivered in a finely divided powder state, its absorption is often faster than from a solid tablet or capsule.
• Specialized Uses: Suspensions are essential for topical lotions, certain vaccines, and X-ray contrast agents (e.g., Barium sulfate)

The rationale for developing a nanosuspension goes beyond the above points. It is specifically aimed at overcoming severe bioavailability issues for extremely poor water-soluble drugs by leveraging the principles of nanotechnology. The goal is to achieve high absorption of a solution while keeping the stability of a suspension.

1. Massive Bioavailability and Dissolution Enhancement

• Increased Surface Area: Reducing the particle size to the nanometer range causes an enormous increase in the total surface area. Since the dissolution rate is directly proportional to surface area (Noyes-Whitney equation), this leads to rapid dissolution that mimics a soluble drug.
• Increased Solubility: The ultra-small size also fundamentally increases the drug's saturation solubility (Ostwald-Freundlich effect), further accelerating absorption.

2. Versatility for Difficult Drugs

• Solving the "Brick Dust" Problem: Nanosuspensions are ideal for drugs that are poorly soluble in both water and organic solvents, which are often impossible to formulate using traditional methods.
• High Drug Load: They consist almost entirely of pure drug nanocrystals, allowing for a very high concentration of the active ingredient in a small dose volume.

3. Improved Pharmacokinetic Profile

• Faster Onset: The rapid dissolution leads to faster absorption and a quicker time to therapeutic effect.
• Reduced Food Effect: Enhanced absorption can lessen the impact of food on the drug's uptake, leading to more consistent dosing.
• Passive Targeting: In some applications (like cancer therapy), the nanoparticles can preferentially accumulate at disease sites (Enhanced Permeability and Retention - EPR effect).

4. Route of Administration Flexibility

Nanosuspensions enable safer and more effective delivery through various routes:

• Intravenous (IV): Allows for the IV injection of poorly soluble drugs without toxic co-solvents, significantly improving safety.
• Other Routes: The small, non-irritating particle size is suitable for specialized delivery via ocular, pulmonary, or topical routes.

5. Conversion to Stable Solid Forms

The nanosuspension liquid can be dried (e.g., by freeze-drying or spray-drying) to produce solid-state nanocrystal formulations (tablets, capsules) with excellent long-term stability and high patient compliance.

METHODOLOGY:

The methodology for oral liquid formulations involves a systematic approach to designing, preparing, and evaluating liquid medications that are administered by mouth. These formulations, which include solutions, suspensions, emulsions, syrups, elixirs, linctus, oral drops, and mixtures, are designed for patients who may have challenges swallowing solid forms like tablets or capsules, such as pediatric or geriatric patients.vicihealthsciences+2?

Key Steps in Oral Liquid Methodology

• Formulation Design: This involves selecting the active pharmaceutical ingredient (API) and suitable excipients (like solvents, sweeteners, preservatives, flavorings, and colorants) that are compatible and stable together, ensuring overall safety, efficacy, and palatability of the product.hello-pharma?
• Solubility and Compatibility: The API and excipients should be soluble or compatible for suspensions or emulsions, ensuring a stable and homogeneous preparation.hello-pharma?
• Preparation and Mixing: Depending on the type of oral liquid, the product may be a solution (fully dissolved API), suspension (finely dispersed API), or emulsion (two-phase system, such as oil-in-water). Advanced mixing and homogenization techniques are used to achieve uniformity and stability.
• Stability Testing: Rigorous physical, chemical, and microbiological stability studies are conducted to ensure the oral liquid maintains its quality over time.hello-pharma?
• Packaging and Labeling: The prepared liquid is filled into appropriate containers, sealed, and labeled with essential information for safe use.

Here are some common mixing techniques:

1. Homogenization:

• Homogenization ensures the uniform distribution of the API and excipients throughout the formulation. High shear mixers or homogenizers are commonly used for this purpose.

2. Agitation:

• Agitation is essential for achieving proper dissolution and preventing the settling of solid particles. Magnetic stirrers or propeller mixers are frequently used for this step.

3. Shear Mixing:

• Shear mixers generate a controlled flow pattern, aiding in the dispersion of insoluble components.

4. Ultrasonication:

• Ultrasonication uses high-frequency sound waves to create intense agitation, facilitating dissolution and dispersion of ingredients.

5. Batch Size Considerations:

• Adjust mixing parameters (speed, time, etc.) based on the batch size to ensure uniformity.

In nano-suspension some common techniques:

Fig 4.NANOSUSPENSION PREPARATION TECHNIQUES (a)

Nanosuspension preparation techniques are generally categorized into two main approaches: Top-Down Technologies and Bottom-Up Technologies. The goal of both is to reduce the drug particle size to the nanoscale (typically below 1 /mu m) to enhance dissolution rate, solubility, and ultimately, bioavailability, especially for poorly water-soluble drugs.

Here is a detailed breakdown of the main techniques:

Fig 5.NANOSUSPENSION PREPARATION TECHNIQUES (b)

I. Top-Down Technologies (Size Reduction)

These techniques start with larger drug particles and reduce their size through mechanical forces. They are the most common methods used commercially.

1. High-Pressure Homogenization (HPH)

This is a very popular and scalable technique.

Process: The drug powder is first dispersed in an aqueous solution containing stabilizers (surfactants and/or polymers) to form a pre-suspension.

This pre-suspension is subjected to very high pressure (up to 2000 bar) as it is forced through a narrow gap (homogenization valve).

The fluid accelerates to a very high velocity, leading to particle size reduction primarily through cavitation (formation and implosion of vapor bubbles), shear forces, and particle collision. The process is repeated for multiple cycles (e.g., 10-25 cycles) until the desired particle size is achieved.

Fig 6. HIGH-PRESSURE HOMOGENIZATION METHOD

Variants:

DissoCubes® Technology: Uses a gap homogenizer (like a piston-gap homogenizer) under high pressure.

NanoPure® Technology: Often used interchangeably with HPH.

2. Media Milling (Wet Milling)

This is another commercially established technique.

Process: The drug, along with a stabilizer, is placed in a milling chamber containing small, high-density milling media (e.g., polymer-coated ceramic or glass beads).

The media are agitated at high speed by an impeller or rotor.

Particle size reduction occurs due to the continuous impact, attrition (rubbing), and shear between the drug particles, the milling media, and the mill wall.

A cooling system is necessary to dissipate the heat generated during the milling process.

Fig 7. Media Milling (Wet Milling) Method

Advantages: Can achieve very fine particle sizes and is highly scalable.

3. Dry Milling (e.g., Jet Milling, Pearl Milling)

Process: Used to reduce particle size of solid materials without a liquid vehicle, but typically only achieves particle sizes down to the micron range, sometimes requiring further processing (like wet milling or HPH) to reach the nano range.

Fig 8.  Dry Milling (e.g., Jet Milling) Method

II. Bottom-Up Technologies (Particle Assembly)

These techniques involve dissolving the drug and then precipitating it out in the presence of stabilizers to control crystal growth, resulting in nanosized particles.

1. Precipitation Method (Antisolvent Precipitation)

Process: The drug is dissolved in an appropriate organic solvent (which is usually water-miscible).

This drug solution is rapidly added, often drop-wise, into an excess volume of a non-solvent (antisolvent), typically water containing a suitable stabilizer.

The rapid mixing causes supersaturation of the drug in the non-solvent medium, leading to nucleation and controlled crystal growth, resulting in the formation of a nanosuspension.

Fig 9. Precipitation Method (Antisolvent Precipitation) Method

Key Challenge: The presence of residual organic solvents can be a concern and must be minimized or removed.

2. Emulsion/ Microemulsion as Template Method

Process: The drug is dissolved in the oil phase of an oil-in-water (O/W) emulsion, which is stabilized by surfactants.

A large volume of non-solvent (water) is added to the emulsion to extract and/or evaporate the solvent, causing the drug to precipitate out as nanosized particles within the aqueous phase.

Fig 10. Emulsion/ Microemulsion as Template Method

For microemulsion templates, a thermodynamically stable, transparent microemulsion is formed first. The drug precipitates upon dilution with the non-solvent.

Advantages: Can produce very small and uniform particle sizes.

3. Supercritical Fluid (SCF) Techniques

These methods use supercritical fluids, like supercritical carbon dioxide (scCO_2), as a solvent, anti-solvent, or dispersion medium.

Common Variants:

RESS (Rapid Expansion of Supercritical Solution): The drug is dissolved in scCO_2, and the solution is rapidly expanded through a nozzle into a chamber at lower pressure. The sudden drop in pressure causes the drug to precipitate instantly as fine particles.

SAS (Supercritical Antisolvent): scCO_2 is used as an anti-solvent. A solution of the drug in an organic solvent is sprayed into scCO_2. The scCO_2 rapidly extracts the organic solvent, causing the drug to precipitate as nanoparticles.

Fig 11. Supercritical Fluid (SCF) Technique

QUALITY CONTROL TESTS:

In-Process Quality Control (IPQC) Tests