ACTIVE PHARMACEUTICAL INGREDIENT (API), SOLVENTTypical end productsActive Pharmaceutical Ingredients (APIs) for the manufacture of different drugs, such as antibiotics, vitamins and enzymes.

Chemicalcurve:R.I.atRef.Temp.of20˚C

Introduction

After crystallization, the active pharmaceutical ingredient (API) needs to be separated from the mother liquor and impurities. Separation of the API crystals is usually performed by pressure filtration.

Filter cake washing is an important step in pharmaceutical processing, since high purity is a main requirement. Inefficient washing of the API crystals affects the quality attributes of the final drug and may create problems in downstream processing.

Application

Filter cake washing removes the impurities and mother liquor from the filter cake by the application of a miscible and pure washing solvent. The number of washing steps required, and the washing solvent are specific for each process.

The design and operation of cake washing requires thorough evaluation. Solubility of the API in the washing solvent is undesirable as it reduces the product yield. Therefore, the washing solvent must be carefully selected to displace the mother liquor from the cake whilst minimizing product dissolution.

Process understanding is also necessary. The development of washing profiles can help to understand the washing regime, and to find the optimal conditions for the highest washing efficiency.

Refractive index has proven to be a valuable tool for the development, monitoring and control of cake washing operations. Refractive index measurement is used, for example, to understand the impact of variations on the process and on the product, to create washing profiles, and to find the most suitable washing solvent.

Instrumentation and installation

The K-Patents Pharma refractometer PR-43-PC provides an accurate refractive index measurement with excellent repeatability. The refractometer is ideal for the development and in-line monitoring of cake washing operations.

The optional Laboratory Test Cuvette (LTC) for the K-Patents Pharma Refractometer offers the opportunity to use the same instrument throughout the entire development process. At laboratory scale, the refractive index of pure solvent and saturated solvents can be studied and used as reference to determine the optimal washing conditions. The refractometer can also be used to find the washing profile of the

Production of an Active Pharmaceutical Ingredient (API)Pharmaceuticals and Biochemicals |

PHARMACEUTICALS AND BIOCHEMICALS

FILTER CAKE WASHINGAPPLICATION NOTE 6.01.04

6.01.04. FILTER CAKEWASHING

process, which can be used as a fingerprint of the process during scale-up operations, and as a tool for troubleshooting (Figure 1).

At pilot and full-scale, the K-Patents refractometer is installed after the filter in the spent solvent line to monitor in real-time the refractive index of the liquid. Because each liquid has a different refractive index

value, the refractometer can detect immediately the interface between the mother liquor and washing solvent. This indicates the end-point of washing and reduces washing time and the amount of solvent used.

The K-Patents refractometer is delivered factory calibrated and it does not require re-calibration. The measurement by the refractometer is not affected by bubbles or suspended particles, making it perfect for liquid-solid operations. Moreover, verification is easily performed with standard refractive index liquids.

When many instruments are required, the K-Patents Multichannel User Interface (MI) connects up to 4 refractometers, thus reducing the investment cost. The MI provides user authentication, electronic records, data logging, event log and audit trail, all in compliance with pharmaceutical requirements.

The K-Patents Pharma Refractometer is the ideal in line process analyzer in accordance with the PAT framework. Monitoring the filter cake washing operation with the K-Patents refractometer helps to obtain a clean cake while meeting the economic, production and quality requirements of pharmaceutical processing.

Instrumentation DescriptionK-Patents Pharma refractometer PR-43-PC for hygienic installations. The PR-43-PC is installed inthe main processing line or vessel and no by-pass arrangements are required. Optional laboratorytest cuvette (LTC) for off-line laboratory testing and validation.

K-Patents Sanitary Compact Refractometer PR-43-AC for hygienic installations in small pipe linesizes of 2.5 inch and smaller. The PR-43-AC refractometer is installed in the pipe bend. It is anglemounted on the outer corner of the pipe bend directly, or by a flow cell using a 3A Sanitary clamp,I-clamp or Varinline® connection.

K-Patents Sanitary Probe Refractometer PR-43-AP for hygienic installations in large pipes, tanks,cookers, crystallizers and kettles and for higher temperatures up to 150°C (300 °F). The PR-43-AP refractometer is installed in the pipe line or vessel through a 2.5 inch or 4 inch Sanitary clamp,I-clamp, APV Tank bottom flange or Varinline® connection.

User Interface Selectable multichannel MI, compact CI or a web-based WI user interface options allow the user to select the most preferred way to access and use the refractometer measurement and diagnostics data.

Measurement range Refractive Index (nD) 1.3200 – 1.5300, corresponding to 0-100 % by weight.

Figure 1. Washing profile of an API crystal cake. After installation, the data from the K-Patents refractometer reveals that the washing solvent and conditions are not optimal, which leads to reduced yield.

Production of an Active Pharmaceutical Ingredient (API)Pharmaceuticals and Biochemicals |

PHARMACEUTICALS AND BIOCHEMICALS

FILTER CAKE WASHINGAPPLICATION NOTE 6.01.04