Support Materials

    We have a range of resources designed to support companies in their understanding of both continuous processing and NiTech’s technology. These include papers and presentations, videos, webinars and FAQs – all updated on an ongoing basis.

    Application Examples

    NiTech Solutions download training presentationAcademic Characterisation Applications

    (933Kb presentation pdf)

    NiTech Solutions download training presentationAcademic Crystallization Applications

    (1Mb presentation pdf)

    NiTech Solutions download training presentationAcademic Reaction Applications

    (1Mb presentation pdf)

    NiTech Solutions download training presentationIndustrial Crystallization Applications

    (629Kb presentation pdf)

    NiTech Solutions download training presentationIndustrial Reaction Application

    (340Kb presentation pdf)

    NiTech continuous crystallization for production of high quality CBD isolate

    Overview of NiTech technology and benefits

    NiTech DN15 Key Features – continuous manufacturing

    The Centre for Process Innovation (CPI) and Croda video showing the successful outcome of a project to develop a continuous process for a range of market-leading surfactants using NiTech technology

    NiTech – How can continuous manufacturing help me?

    NiTech External Specifications

    Technology Overview

    Technology Downloads

    Download A-Z NiTech technical papers

    Technology Webinars

    NiTech Webinar 1:
    Current Processing Issues

    NiTech Webinar 2:
    Why Do We Need to Flow

    NiTech Webinar 3:
    The NiTech Solution for Reactions

    NiTech Webinar 4:
    The NiTech Solution for Crystallization

    FAQ

    Company and Product Q&A

    Who is NiTech Solutions?

    NiTech Solutions Ltd is a UK-based private company that provides continuous process technology solutions for reaction and crystallization unit operations, using its patented baffled vessel technology together with its extensive process know-how.

    What are the key problems with existing process techniques?

    Stirred tank reactors (STRs) have been the workhorse in manufacturing chemicals, pharmaceuticals and food products since records began, and face the century old problem that mixing gets worse with increasing scale. This un-scalable mixing in stirred tanks is the root of the problem, meaning that one cannot repeat what was obtained in labs, e.g. a 30 min reaction in the lab would require a process time and associated process inventory of over 30 hrs. Because of this poor mixing in stirred tanks:

    • temperature gradients lead to heat transfer constraints; and
    • concentration gradients result in mass transfer constraints.

    These can be problematic for reactions:

    • when reaction heat cannot effectively be removed, side reactions proceed, requiring post-reaction unit operations to separate and purify products, leading to an increase in energy consumption and waste generation;
    • when reactants are not uniformly distributed in the reactors, sub-stoichiometric reactions proceed, requiring post-reaction unit operations to separate and purify products as above;
    • post-unit operations mean significant factory inventory and carbon footprints together with associated capital/running costs; and
    • higher costs per kg product are the likely outcome.

    These can also be problematic for crystallization processes as:

    • temperature gradients affect the control of cooling rate and operational path – overshooting the metastable zone leads to spontaneous nucleation and small crystals that do not grow;
    • significantly longer filtration time is often the direct outcome due to uneven size distribution;
    • impurity may increase due to agglomeration and solvent entrapment; and
    • inconsistent product quality requires many post-crystallization unit operations to achieve the required crystal properties.

    What are the remedies for existing process techniques?

    Better mixing and plug flow can be achieved in STRs when operated in a cascade format. In theory, an infinite number of STRs are required to achieve plug flow; in practice, the more the better, but in reality, it is a balance of costs and the degree of plug flow achievable – as every tank added is associated with a £ sign covering both capital and running costs. Cascade STRs are the norm in process industries.

    What is the essence of NiTech’s technology?

    The essence of NiTech reactor technology enables kinetic (theoretical) reaction times obtained in labs to be executed in pilot and full scales, due to uniform mixing and plug flow achieved through the combination of fluid oscillation and baffle restrictions. By doing so, it:

    • delivers consistent product quality (eliminating post-reaction unit operations);
    • shrinks reactor volumes (smaller);
    • reduces plant inventory (safer); and
    • lowers energy utilisation and waste generation (greener).

    The essence of NiTech crystallizer technology enables the control of both mixing and temperature (cooling) simultaneously in labs as well as pilot and full scales, due to uniform mixing, plug flow and superior heat transfer rate achieved. By doing so, it:

    • delivers consistent crystal properties (eliminating post-crystallization unit operations);
    • enables uniform crystal sizes, reducing filtration time and the potential of impurity due to solvent entrapment;
    • shrinks crystallizer volumes and reduces plant inventory; and
    • lowers energy/solvent utilisation (greener).

    NiTech technology makes the right product every time.

    What are the key differences between NiTech reactors and other flow reactors, including microreactors?

    Near plug flow can be attained in turbulent flows – this mechanism is the driving force for mixing in other types of flow reactors. As high net flow Reynolds numbers (high flow rates) are required to achieve turbulent flows in tubular reactors, only shorter reaction times, e.g. <10 mins, can be accommodated or forbidden reactor lengths would be needed. Loop reactors, coil reactors and jet reactors belong to this category.

    In theory, mixing in microreactors should follow the above principle, but this would lead to an infinitely long reactor length due to every small diameter of the channel/tube (in micrometers). In contrast to the operation of other flow reactors above, small flow rates in creeping flow range are utilised in microreactors. Diffusion is thus the main driver for mixing that is aided by flow around bends and other restrictions within the internal configuration of the channels/tubes.

    Mixing in NiTech reactors is achieved by eddy motions that are generated by the combination of fluid oscillation and the presence of baffles and is not controlled by net flow as in other flow reactors. The unique feature of decoupling net flow from mixing allows the accommodation of longer reaction/process times, e.g. 2 hours. It should be noted that NiTech’s tubular baffled reactor (TBR) technology can be used for reaction times from seconds to a few minutes.

    In terms of process classifications, microreactors have very high specific surface areas and are good for reactions with high exotherms and have been used for liquid-liquid and some gas-liquid reactions. Solids are barriers for diffusion, hence microreactors seldom handle solids, while NiTech reactors are good for processes involving solids-liquid, liquid-liquid and some gas-liquid.

    What steps are typically involved in installing a production-scale continuous unit?

    1. Two-way non-disclosure agreement (NDA) is signed;
    2. The problems associated with the current batch operation are identified, analysed and understood;
    3. Does the client have lab data of the process or chemistry? If so, the data can be used for understanding the kinetics and process parameters affecting kinetics. A feasibility project contract using NiTech’s continuous reactor is proposed to confirm the kinetics in continuous operation, explore the parameter effects on kinetics as well as the operating windows and establish process improvements and benefits;
    4. If the client does not have lab data for their process, a feasibility project contract will also be proposed using NiTech batch reactors to establish reaction kinetics and the associated parameter effects, and identify process improvements and benefits. A follow-on feasibility proposal will then be offered to achieve the objectives of (3);
    5. Process benefits and potential cost savings are assessed based on the trial data from either (3) or (4). A business case for converting to continuous is now established;
    6. Pilot-scale trials are then conducted on a made-to-order unit, based on the outcomes of the lab-scale feasibility contracts above in order to verify and enhance the benefits, explore operating windows and run the pilot-scale unit in a manufacturing environment by the production team;
    7. A production-scale unit is designed, manufactured, installed and commissioned, based on learnings and confirmations from pilot-scale trials.

    Does NiTech manufacture its own units?

    No, this is done under licence by partner Alconbury Weston Ltd (AWL), based in Stoke-on-Trent, UK.

    How are trials/feasibility studies conducted?

    This is done through NiTech’s technology partners across the world or at customers’ sites using purchased or rented NiTech lab-scale units. Here are the general steps to get involved:

    1. A two-way non-disclosure agreement (NDA) between NiTech and the client is signed;
    2. A telcon/skype meeting is arranged so that NiTech understands the process, the problems and outlines the preliminary programme for lab trials;
    3. A two-way NDA between the client and NiTech’s technology partner is signed;
    4. A feasibility contract is viewed and signed containing what needs to be done and the costs;
    5. Lab-scale feasibility studies of the client’s chemistry are carried out in NiTech reactors to identify/confirm process kinetics, establish parameters effects on kinetics and realise process improvements and benefits;
    6. Personnel from the client’s company are welcome to join/see the trials;
    7. Regular telcons take place to exchange information, inform progress and outline next steps;
    8. A final report is submitted at the end of the scheduled trial period, containing the scales for pilot and manufacturing operation, the associated costs and lead times.

    Where are NiTech’s agents and technology partners?

    NiTech has agents and technology partners worldwide, including:

    • CMAC, UK
    • CPI, UK
    • MEPI, France
    • SAS Pivert, France
    • RISE, Sweden
    • Purdue University, USA
    • Bernard Lavorel, Europe
    • Relex Process Consultancy Ltd, Israel
    • E-Zheng Technology Company, China

    More agreements are being finalised and will be added to the list.

    What lab units are available?

    NiTech offers a variety of lab units:

    Batch Screening/Evaluating Reactor and Crystallizer
    • Glass DN15 (175 mL)
    • Glass DN25 (100 mL) and DN40 (250 mL)
    • Glass or steel DN60 (3.2 L)

    The glass units are suitable for temperatures up to 100⁰C (optional extra of 150⁰C) and ambient pressure. The 316 L steel variant can handle pressures up to 10 bar.

    Continuous Lab Reactor and Crystallizer (Glass)
    • DN15 Lite (1.25 L, 30 mins)
    • DN15 Standard (2.5 L, 60 mins)
    • DN15 Plus (3.5 L, 90 mins)

    Temperatures up to 100⁰C, pressures up to 3 bar can be achieved on the tube side and up to 1 bar on the jacket side. The glass is borosilicate and the wetted parts are PTFE and PEEK. Optional extras include higher temperature (150⁰C), on-board integrated peristaltic pumps and bespoke feed and instrument collars.

    Continuous Lab Reactor and Crystallizer (Steel)
    • DN15 Lite HP C22 (1.25 L, 30 mins)
    • DN15 Lite HP 316L (1.25 L, 30 mins)
    • DN15 Standard HP 316L (2.5 L, 60 mins)
    • DN15 Standard HP C22 (2.5 L, 60 mins)
    • DN15 Plus HP 316L (3.5 L, 90 mins)
    • DN15 Plus HP C22 (3.5L, 90 mins)

    These units are suitable for temperatures up to 150⁰C and pressures up to 10 bar, with higher temperature (200⁰C) and higher pressure (25 bar) on request. Sight glasses are included.

    The nominal flow rate for the continuous units is 40 mL/min based on residence times between 30 and 90 mins for lab-scale experiments. This can be increased or decreased depending on chemistry.

    For production units, the flow rates range from 30 to 120 L/min.

    What is the company’s business model?

    NiTech provides clients with continuous reaction and crystallization solutions for their existing batch processes. NiTech’s business model consists of:

    • Selling laboratory, pilot- and commercial-scale units;
    • Providing process solutions to clients’ chemistry/processes; and
    • Licensing full-scale patented manufacturing units.

    How many NiTech reactors and crystallizers have been installed?

    More than 50 NiTech units have been installed since 2005 for academic, research and commercial organisations across the world. These range from small-scale lab units for R&D purposes to pilot and full-scale manufacturing units. Some specific cases are available on our website.

    Applications Q&A

    The following is a list of typical questions for initially assessing the suitability of a process for NiTech technology.

    What overall process time is suitable?

    NiTech technologies are best suited for a range of intrinsic reaction times from seconds to a few hours. Typically, residence times of up to 120 mins can be done in one unit, for longer intrinsic reaction times, two or more units are better in a cascade fashion. Note that intrinsic reaction time refers to the process time without heat or/and mass transfer constraints, and is often indicated by lab test data, not data from production units.

    The pie chart below illustrates the reaction time distributions for a large number of chemicals, pharmaceuticals and food products.

    NiTech reaction time distributions

    What phases of chemical processes are suitable?

    The eddy mixing current in NiTech technologies is propagated downstream by the incompressibility of a fluid or a mixture of fluids; therefore, the dominant phase in any chemical processes must be aqueous. The viscosity of the main phase should generally be lower than 300 cP. A second phase of either solid slurry, gas or liquid of various viscosities can then be added along the length of NiTech reactors, depending on their physical properties, e.g. typically 25% w/w of solids, and 10% v/v of gas.

    NiTech technologies are suitable for processes of liquid-liquid, solid-liquid, some gas-liquid, and some gas-liquid-solid processes, e.g. hydrogenation.

    Can the technology be applied to biological systems?

    Yes, because the mixing is uniform, the shear rate is lower than that generated by impellors, which is good for shear-sensitive cells.

    Can the technology be applicable to photo-chemical processes?

    Yes, NiTech technologies enable light provision in direct contact with process fluids along the reactor, this allows the delivery of a combination of increasing or decreasing or constant light intensity and wavelength along the reactor, achieving controlled photo-catalysis or reactions.

    What types of crystallization processes can NiTech crystallizers handle?

    NiTech crystallizers are suitable for anti-solvent and cooling crystallization processes. In terms of cooling crystallization, it offers the simultaneous control of scale, independent mixing and temperature distribution that cannot be achieved in traditional batch crystallizers. In terms of anti-solvent crystallization, NiTech crystallizers provide intensive mixing at the point of contact between solvent and anti-solvent, are able to suspend crystal particles evenly along the crystallizers, leading to narrow crystal size distributions. NiTech crystallizers are, however, not suitable for evaporation crystallization.

    We heard about encrustation in tubular crystallizers, how is encrustation prevented in NiTech crystallizers?

    Encrustation is caused by uncontrolled nucleation, often when the metastable zone is crossed randomly in batch industrial-scale crystallizers or when the combination of seed properties (seed mass and seed size) is incorrect.

    Seeding is the norm in most pharmaceutical manufacturing processes to overcome unexpected and uncontrolled primary nucleation from happening. Likewise, spontaneous nucleation should generally be avoided in NiTech crystallizers, except for some inorganic crystallizations. Encrustation can be completely eliminated with the correct combination of seed size and seed amount.

    Can the same NiTech unit handle reactions as well as crystallizations?

    Yes, the same NiTech unit can do both reactions and crystallization, where one temperature zone is normally used for reactions, several temperature zones are created in crystallization. For reactions, reactants can be added into a NiTech reactor at different locations along the length of the reactor, either collectively or individually. Products can also be removed in-situ during the reaction or at the end; this adds to the flexibility. For crystallization, seeds can be precisely added just after the saturation – linking crystallization science with operation.

    It is the combination of uniform mixing and temperature control that is the essence for both reactions and crystallization.

    What process data is required for the initial assessment?

    For reactions
    • What are the problems with the existing process, e.g. too much heat, mass transfer, pH, etc?
    • Physical properties of reagents, solvents, catalyst and products, as well as their phase status
    • Process details, e.g. reaction kinetics, concentration profiles, process procedures, mass balances, energy data
    • Throughput
    • Operating temperatures and pressure ranges
    • Conversion and yield
    • Batch time and volumes
    • Heat of reactions, if any
    • Is any gas generated?
    • Is reflux used?
    • Solid loading, if any
    • What post-reaction processes are used?
    For crystallization
    • What are the problems in the current operation, e.g. wide size distribution, filtration too long, high impurity, etc?
    • Throughput
    • Solubility curve and metastable zone width, if any
    • Cooling or anti-solvent process?
    • Starting, nucleation and final temperatures
    • What is the solid ratio or solid loading?
    • Are seeds used? If so, what seed sizes and loading? If not, how is nucleation initiated?
    • Current crystallization/process time and crystallizer volume
    • Physical properties of solvents and solute
    • What are the target crystal properties?
    • How is filtration done and at what temperature?
    • How is washing done and at what temperature?
    • What is the ratio of solvent to antisolvent?

    Presentations and Papers

    Download A-Z NiTech technical papers

    What is the fuss about continuous crystallization?

    Download pdf

    Arkema has for the first time achieved the continuous flow synthesis of zeolite NaX. The successful pilot operation (up to 100 l/hour) was performed using a NiTech© continuous oscillatory baffled reactor (COBR).

    Download pdf

    Continuous flow synthesis of zeolite FAU in an oscillatory baffled reactor

    7 January 2020

    Heidy Ramirez Mendoza
    Mafalda Valdez Lancinha Pereira
    Tom Van Gerven
    Cécile Lutz

    Download pdf

    NiTech Solutions
    Corporate Presentation

    2 September 2019

    Download pdf

    Production Strategies for Manufacturing Active Pharmaceutical Ingredients in Oscillatory Baffled Crystallizers

    August 2018

    Purdue University
    Download pdf

    Manufacturing Active Pharmaceutical Ingredients in Oscillatory Baffled Crystallizers

    Collaborative Research in Action – ReMediES Project

    October 2018

    Clive Badman
    Vice President, pre-competitive collaboration, GSK and ReMediES Project Director
    Download pdf

    Collaborative Research in Action ReMediES Project

    Modernizing Pharmaceutical Manufacturing: FDA View

    October 2018

    Janet Woodcock
    Director
    Center for Drug Evaluation and Research
    US Food and Drug Administration
    Download Presentation (pptx)

    An Investigation in Continuous Catalytic Hydrogenation

    February 2018

    Francisca Navarro Fuentes
    CMAC
    Download pdf

    CMAC presentation 12 Feb 2018 An Investigation in Continuous Catalytic Hydrogenation

    Success stories for scaling up industrial flow chemistries

    Flow Chemistry India
    Mumbai, January 2018
    Laurent Pichon
    MEPI president
    Download pdf

    MEPI presentation at Flow Chemistry India

    Continuous Crystallization and Manufacture

    Achema, Frankfurt, June 2015
    Professor Xiong-Wei Ni
    BSc, PhD, CEng, CSci, FIChemE
    Download pdf

    PP-Achema-2015

    Crystallization explained

    26 June 2015
    NiTech Solutions
    Download pdf

    Crystallisation-explained

    Small-Scale Flexible Plants

    Presented at Achema 2015
    TNO

    Download pdf

     

    PP-small-scale-plants

    Advanced processing and COBR technology: A pragmatic approach

    Denis Wray
    Senior Process Technologist
    The Center for Process Innovation

     

    Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer

    Simon Lawton,† Gerry Steele,† and Phil Shering‡
    AstraZeneca Engineering