How to Approach Granulation of Modified-release Drugs

The concept of modified–release (MR) dosage forms materialised as a neighborhood of the merchandise lifecycle management strategy. The drying pipeline of latest molecules compelled pharmaceutical companies to develop new approaches to retain the exclusivity of patented molecules and gain maximum commercial benefits. This strategy became a huge success setting many companies on the trail where they're now considering the MR approach right at the start of the drug development stage.

From a therapeutic perspective, the altered release profile of a drug product does provide a plethora of advantages to the patients.

• It offers a chance to modulate the drug concentration within the body to supply a sustained therapeutic effect over a period.
• Since MR dosages are required to be taken once each day (in most cases), this reduces the dosing frequency significantly, leading to better patient compliance.
• An MR dosage form maintains a steady-state drug plasma concentration within the body, thus avoiding side-effects associated with fluctuations in drug concentration.
• The technique allows controlling the location of drug delivery within the GIT.

 Targeted product profile (TPP)

A successful formulation of MR dosage form begins with a well-defined TPP, and it's supported the subsequent parameters:

• Establishing a dose range of the molecule that's therapeutically active
• Desired dosing frequency
• The desired release profile of the drug (zero-order release or pulsatile release) along side the minimum and maximum drug plasma levels that are within the therapeutic window
• Dosage form

Formulation considerations

1. Active pharmaceutical ingredient (API) – Granulated MR (GMR) dosage form isn't possible for each drug molecule. The API must be assessed for the suitability of preparing an MR formulation supported the subsequent two characteristics:

• The Biopharmaceutical arrangement (BCS) category of a drug molecule gives more information about its solubility and permeability behaviour. An API with good solubility and permeability can dissolve within the body fluids and undergo the biological membranes at the absorption site.
• The dose-solubility ratio of an API helps in selecting an appropriate MR technology.

1. Release modifying ingredient – After API, it's the second most vital ingredient of GMR formulation that helps to realize the modified drug release profile. the subsequent two sorts of materials are typically used as release modifiers.

• Polymers – These are the foremost commonly used materials for modifying the drug release profile. Depending upon the physicochemical and biopharmaceutical properties of the drug and therefore the process requirement, either a polymer or a mix of polymers are often utilized in the formulation. Generally, high viscosity grades of polymers are used. Following parameters must be taken into consideration before selecting a polymer for a GMR formulation:
• The polymer must have reproducible physical properties.
• The polymer shouldn't interfere with the drug’s therapeutic effect.
• The polymer must be chemically compatible with the API.
• Long-chain hydrocarbons – The hydrophobic properties of long-chain hydrocarbons assist in modifying the drug release from the GMR. Examples include wax and fat materials like carnauba , glyceryl behenate, and glyceryl palmitostearate.

Apart from these two, other ingredients are often added to the formulation depending upon the granulation method used for the manufacturing. All the ingredients selected must be compatible with one another .

Dosage performance factors

The modified drug release pattern is that the sole factor that distinguishes MR dosage forms from the immediate-release ones. Naturally, it’s essential to possess adequate knowledge of the drug release mechanism and therefore the associated factors before the formulation scientists start performing on the formulation.

Drug release mechanism – There are various drug release mechanisms from the GMR, like diffusion, swelling, erosion, and dissolution. It are often one mechanism or a mixture of those . a radical understanding of the discharge mechanism helps the formulation scientists to style a formulation with the specified TPP. the character of the polymer and its behaviour within the release medium also contribute to the drug release mechanism.

Drug release pattern and predictability – the discharge of drug molecules from the dosage form are often described by different mathematical equations. One such equation referred to as Fick’s first law describes the diffusion of drug molecules. It relates the quantity of fabric flowing through a unit cross–section as follows:

 

Where    J = diffusion flux

    D = diffusion coefficient or diffusivity

    C = concentration

              X = distance of movement

With the knowledge of the drug-release mechanism and therefore the available mathematical equations, it becomes easy for the formulation scientists to convert the drug-release process from the dosage form into a theoretical model and understand its kinetics.

Reproducibility of drug-release pattern – The drug-release pattern of an MR dosage form is evaluated by using in–vitro dissolution methods as defined by regulatory guidelines. For a satisfactory performance of an MR dosage form, the rules recommend a minimum of three dissolution time points:

1. An early time point to make sure that there's no dose dumping

1. A middle time point for control of release profile

1. The last time point to make sure that a minimum of 80% of drug release has occurred

Besides, the subsequent two factors must be considered during dissolution testing of an MR dosage form.

• In vitro-in vivo correlation (IVIVC) – it's a predictive mathematical model that describes a relationship between an in vitro property of a dosage form (e.g., drug dissolution profile) to an in vivo response elicited by an equivalent dosage form (e.g., drug’s extent of absorption). Establishing an IVIVC significantly cuts down the amount of bioavailability/bioequivalence studies needed at the initial development and approval process. 
• Dose dumping – Ideally, the drug-release from an MR dosage form shouldn't be suffering from the presence of food and alcohol. This becomes particularly important for drugs with a narrow therapeutic index where an entire release of dose before the intended time and place can cause potentially toxic drug levels within the body. An in vitro dissolution study can address this issue.

Different approaches used for GMR processing

1. A standard tablet with an instantaneous release profile are often converted into an MR dosage form by adding a drug-release retarding polymer within the formulation.
2. A foam binder technology are often utilized in which a foamed binder solution is directly added to the dry powders within the granulator.
3. For drugs with a brief half-life, MR formulation are often prepared within the sort of bilayer tablets. One layer of this tablet immediately releases the drug (about 60%) to realize adequate plasma levels. the opposite layer releases the remainder of the drug at a slower rate to take care of the effective drug concentration within the body for a extended time.
4. Spray drying has been used for the preparation of MR dosage forms. In this, an answer or suspension of the drug is pumped and atomised into a drying chamber under a controlled airflow to supply granules.

Takeaway

Although bringing a granulated MR dosage form on the market offers various commercial benefits to the pharma companies, developing such a formulation is sort of a task, calling for multiple iterations and considerations of the key materials, analytical, and manufacturing processes. However, watching the present granulation techniques and therefore the rapid advances during this area, it's safe to assume that developing a granulated MR dosage form won’t be a challenge anymore within the near future.

 

Reference  

https://pharma-trends.com/2021/03/11/how-to-approach-granulation-of-modified-release-drugs/

 

Pharmaceutical Solutions

Website:

https://www.acg-world.com/