TOPIC 3.2: Filtration (API Isolation)

What is filtration?

• The desired drug substance (ie. API) is synthesized via chemical reaction and remains in a dissolved state within a solution in the batch reactor

• FIltration is the separation of solids from a solid-liquid mixture (slurry) by means of a porous medium or screen which retains the solids while allowing the liquid to pass

  • In Pharmaceutical application, solid is the valuable product (ie. API) and liquid is the waste (ie. mother liquor)

    • Results in separation of the solids as wet cake → need to wash and dry to yield high purity API

What is cake filtration?

• A solid-liquid process where slurry is forced through a filter medium with pores smaller than the slurry’s solid’s particle size

• The liquid (ie. filtrate) passes through while the solids get retained, accumulating as cake on the medium

Cake Filtration — Key Characteristics

• Used for slurries with a high proportion of solids.

• Solids build up as a cake, increasing thickness and flow resistance over time.

• Lab equipment: Büchner funnel and flask.

• Industrial equipment: Agitated Nutsche Filter.

Cake Filtration — Principle (Why is the initial stage critical?)

The initial stage is critical as:

1. Flow rate is highest at the start since the resistance is minimum

2. Too-high initial flow can plug filter pores → greatly increasing resistance

3. The arrangement of the first particle layers greatly influences the entire cake structure

Cake Filtration — Principle (Effects of solids concentration)

LOW concentration	HIGH concentration
Particles penetrate and block pores (blocking filtration) → higher cake resistance	Particles quickly bridge over pores → shields them → lower cake resistance

Delayed cake filtration

• During regular filtration, resistance to filter cake progressively increases → reduces rate of filtrate flow

• Delayed cake filtration delays / reduces build-up of cake by limiting cake thickness

• Cake thickness remains constant → allows constant filtrate flow

• Agitated Nutsche filter is needed

  • Comes with an agitator → thickness is limited to the clearance between agitator blades and filter medium

    • Filtrate flows through cake at a constant rate BUT solids are retained in the suspension

    • BUT if solid concentration starts to increase, particles will start to make permanent physical contact with each other → ↑ resistance to flow → ↓ filtrate flow

Rate of Filtration — Formula

dV/dt ∝ (A △P) / (rμL)

Rate of Filtration — Constant Pressure vs Constant Rate

PARAMETER	CONSTANT PRESSURE FILTRATION	CONSTANT RATE FILTRATION
Filtration Area (A)	Constant (Dependent on equipment design)
Resistance (r) & Filtrate Viscosity (µ)	Constant (Dependent on physical properties of filter medium, cake and filtrate)
Thickness (L)	Increases (As filtration process proceeds)
Differential pressure (ΔP)	Kept constant	Increases to keep dV/dt constant
Flow rate dV/dt	Decreases eventually	Kept constant
	More frequently adopted for practical reasons → easier to operate

Factors Affecting Rate of Filtration (Cycle Time)

FACTOR	EFFECT(S)
Resistance, r	Include filter medium and cake resistance Filter medium resistance depends on type, material and pore size Cake resistance depends on solid particle size, cake porosity, particle density and shape ↑ Solid concentration in slurry → ↓ cake resistance ↓ Resistance = ↑ rate of filtration
Thickness, L	Includes filter medium and cake resistance ↓ Thickness = ↑ rate of filtration
Filtration Area, A	↑ Filtration Area = ↑ rate of filtration
Filtrate Viscosity, µ	↓ Viscosity of filtrate = ↑ rate of filtration
Pressure difference across cake and filter medium, ∆P	Driving force for filtrate flow Pressure drop can be achieved by: Gravity (slurry head pressure → depends on slurry density) Vacuum (on the filtrate side) Pressure (pump slurry into filter) ↑ Differential pressure = ↑ rate of filtration

Filter Medium

• Acts as a support for the filter cake while the initial layer of cake is the true filter

• MUST satisfy cGMP requirements:

  • Sintered stainless steel, polypropylene, or 100% cellulose material (Non shedding type)

  • High mechanical strength, and chemical resistance

  • Able to withstand sanitization temperatures of 80 °C during Cleaning-in-place (CIP)

“Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance”

• Should offer minimum resistance to filtrate flow 

• Easy cake removal is essential for maximizing product yield recovered

Washing of Filter Cake

• To remove traces of mother liquor, unreacted starting material, by-product or impurities from the cake

  • Directly reduces the impurity level in the final drug substance

  • Prevents the crystals from re-dissolving in the residual mother liquor during drying

• Washing liquid MUST have:

  • Maximum solubility of the unwanted impurities (to prevent crystallization of the impurities)

  • Minimum solubility of the product (to prevent product loss to the washes)

  • Low boiling point and inert to cake (improves drying productivity)

• Washing is done in 2 stages:

1. Displacement washing – Mother liquor is directly displaced from cake surface by washing liquid (removes 90% of filtrate)

2. Diffusion washing – Remaining mother liquor diffuses into the washing liquid from the less accessible voids

• Re-slurry washing – Cake is re-suspended in fresh washing liquid to form a slurry → filter again 

• Channeling is the main problem encountered during cake washing

  • Washing liquid forms preferred paths ("channels") through the cake, leaving some areas unwashed → incomplete washing 

  • Can use lower pressure during washing than during filtration OR use an agitator to smooth the surface