Ultrasonic Pengolahan Nano Partikel untuk Farmasi

Probe-type sonicators play a crucial role in pharmaceutical research and manufacturing by providing a powerful and controlled means of achieving particle size reduction, cell disruption, and homogenization. Sonicators utilize ultrasonic waves to generate cavitation, resulting in the formation and collapse of microscopic bubbles. This phenomenon generates intense shear forces and shock waves, effectively breaking down particles or disrupting cells.

Here are some key aspects of the use of probe-type sonicators in pharmaceutical applications:

  • Particle Size Reduction: Probe sonicators are employed to reduce the particle size of active pharmaceutical ingredients (APIs) or other compounds. A small and uniform size of particles is vital for enhancing bioavailability, dissolution rates, and overall efficacy of pharmaceutical formulations.
  • Cell Disruption: In biopharmaceutical research, probe sonicators are utilized for cell disruption to release intracellular components. This is particularly important for the extraction of proteins, enzymes, and other biomolecules from microbial cells or cultured mammalian cells.
  • Homogenization: Homogenization of pharmaceutical formulations is essential for ensuring uniform distribution of ingredients. Probe sonicators aid in achieving homogeneity by breaking down agglomerates and dispersing components evenly.
  • Nanoemulsion and Liposome Formation: Sonication is used to create stable nanoemulsions and liposomes in pharmaceutical formulations. These nanoscale delivery systems are employed for drug delivery to enhance solubility and bioavailability.
  • Quality Control and Process Optimization: Sonication is a valuable tool for quality control in pharmaceutical manufacturing. It helps in optimizing processes by ensuring consistent particle size distribution and homogeneity, contributing to batch-to-batch reproducibility.
  • Drug Formulation and Development: During drug formulation and development, probe sonicators are utilized to prepare stable suspensions, emulsions, or dispersions. This is critical for designing pharmaceutical products with desired physical and chemical properties.

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Ultrasonically agitated reactor for improved peptide synthesis.

Ultrasonically agitated reactor for improved and accelerated synthesis. The picture shows the ultrasonicator UP200St in a stirred glass reactor.

Nanomaterials dalam Farmasi

Ultrasonic technologies play a pivotal role in the preparation, processing, and functionalization of nanomaterials in pharmaceutical research and manufacturing. The intense effects of high-power ultrasound, including acoustic cavitation, contribute to breaking agglomerates, dispersing particles, and emulsifying nano-droplets. Hielscher high-performance sonicators provide a reliable and efficient solution for pharmaceutical standards, ensuring safe production and facilitating scale-up without additional optimization efforts.

Pengolahan Nanomaterials

Nanomaterials, particularly nanoparticles, have revolutionized drug delivery in pharmaceuticals, offering a proven method for administering active agents orally or through injection. This technology enhances the efficiency of drug dosing and delivery, opening novel avenues for medical treatments. The ability to deliver drugs, heat, or other active substances directly to specific cells, particularly diseased cells, marks a significant advancement.

In cancer therapy, nano-formulated drugs have demonstrated promising results, leveraging the advantage of nano-sized particles to deliver high drug doses directly to tumor cells, maximizing therapeutic effects while minimizing side effects on other organs. The nanoscale size allows these particles to pass through cell walls and membranes, releasing active agents precisely at targeted cells.

Processing nanomaterials, defined as particles with dimensions less than 100nm, presents challenges that demand higher efforts. Ultrasonic cavitation emerges as a well-established technology for deagglomerating and dispersing nanomaterials. Carbon Nanotubes (CNTs), especially Multi-Walled Carbon Nanotubes (MWCNTs) and Single-Walled Carbon Nanotubes (SWCNTs), showcase unique properties, offering a large inner volume for encapsulating drug molecules and distinct surfaces for functionalization.
 

Dosis nanotube karbon berdinding tunggal yang disatukan secara sonokimia (SWNTs / SWCNTs)

Sonochemical production of SWCNTs. Silica powder in a solution of ferrocene-xylene mixture has been sonicated for 20 min. at room temperature and under ambient pressure. Sonication produces high-purity SWCNTS on the surface of the silica powder. (Jeong et al. 2004)

 

Functionalized Carbon Nanotubes (f-CNTs) play a crucial role in enhancing solubility, allowing efficient tumor targeting, and avoiding cytotoxicity. Ultrasonic techniques facilitate their production and functionalization, such as the sonochemical method for high-purity SWCNTs. Moreover, f-CNTs can serve as vaccine delivery systems, linking antigens to carbon nanotubes to induce specific antibody responses.
Ceramic nanoparticles derived from silica, titania, or alumina present porous surfaces, making them ideal drug carriers. Ultrasonic synthesis and precipitation of nanoparticles, utilizing sonochemistry, provide a bottom-up approach for preparing nanosize compounds. The process enhances mass transfer, resulting in smaller particle sizes and higher uniformity

Sintesis Ultrasonik dan Pengendapan Nanopartikel

Ultrasonication plays a vital role in functionalizing nanoparticles. The technique efficiently breaks up boundary layers around particles, allowing new functional groups to reach the particle surface. For instance, ultrasonic functionalization of Single-Walled Carbon Nanotubes (SWCNTs) with PL-PEG fragments interferes with nonspecific cell uptake while promoting specific cellular uptake for targeted applications.

Ultrasonik homogenizer memungkinkan dispersi yang effektiv, deaglomerasi dan fungsionalisasi dari nano material

Hielscher lab sonicator UP50H untuk sonikasi volume kecil, misalnya untuk dispersi MWNTs.

Untuk mendapatkan nanopartikel dengan karakteristik dan fungsi tertentu, permukaan partikel harus dimodifikasi. Berbagai nanosystem seperti nanopartikel polimer, liposom, dendrimer, nanotube karbon, titik kuantum dll dapat berhasil difungsikan untuk penggunaan yang efisien di farmasi.

Practical Example of Ultrasonic Particle Fuctionalization:

Fungsi Ultrasonik SWCNTs oleh PL-PEG: Zeineldin et al. (2009) menunjukkan bahwa dispersi nanotube karbon berdinding tunggal (SWNTs) dengan ultrasonikasi dengan fragmen fosfolipid-polietilen glikol (PL-PEG) itu, sehingga mengganggu kemampuannya untuk memblokir serapan nonspesifik oleh sel. Namun, PL-PEG yang tidak terfragmentasi mempromosikan serapan seluler spesifik dari SWNT yang ditargetkan ke dua kelas reseptor yang berbeda yang diungkapkan oleh sel kanker. Perlakuan ultrasonik dengan adanya PL-PEG adalah metode umum yang digunakan untuk menyebarkan atau memfungsikan nanotube karbon dan integritas PEG penting untuk mendorong serapan seluler spesifik dari ligan fungsional nanotube. Karena fragmentasi adalah konsekuensi dari ultrasonication, teknik yang biasa digunakan untuk menyebarkan SWNTs, ini mungkin menjadi perhatian untuk aplikasi tertentu seperti pengiriman obat.
 

Sonication is a highly effective method to modify and functionalize nanoparticles

Ultrasonic dispersion of SWCNTs with PL-PEG (Zeineldin et al., 2009)

 

Formasi Liposome Ultrasonik

Another successful application of ultrasound is the preparation of liposomes and nano-liposomes. Liposome-based drug and gene delivery systems play a significant role in manifold therapies, but also in cosmetics and nutrition. Liposomes are good carriers, as water soluble active agents can be placed into the liposomes aqueous center or, if the agent is fat soluble, in the lipid layer. Liposomes can be formed by the use of ultrasonics. The basic material for liposome preparation are amphilic molecules derived or based on biological membrane lipids. For the formation of small unilamellar vesicles (SUV), the lipid dispersion is sonicated gentlye.g. with the handheld ultrasonicator UP50H (50W, 30kHz), the VialTweeter or ultrasonic cup-horn . The duration of such an ultrasonic treatment lasts approx. 5 – 15 minutes. Another method to produce small unilamellar vesicles is the sonication of the multi-lamellar vesicles liposomes.
Mahendar-Pirvu et al. (2010) laporan mendapatkan transferosomes oleh sonicating MLVs pada suhu kamar.
Hielscher Ultrasonics menawarkan berbagai perangkat ultrasonik, sonotrodes dan aksesoris untuk memenuhi persyaratan dari semua jenis proses.
Read more about ultrasonically-extracted and encapsulated Aloe vera extract!

Ultrasonik Enkapsulasi Agen ke Liposom

Liposom bekerja sebagai pembawa untuk agen aktif. Ultrasound adalah alat yang efektif untuk mempersiapkan dan membentuk liposom untuk menjebak agen aktif. Sebelum enkapsulasi, liposom cenderung membentuk gugus karena interaksi pengisian muatan permukaan kepala kutub fosfolipid (Míckova et al 2008. 2008), selanjutnya harus dibuka. Sebagai contoh, Zhu dkk. (2003) menjelaskan enkapsulasi bubuk biotin dalam liposom dengan ultrasonication. Saat bubuk biotin ditambahkan ke dalam larutan suspensi vesikula, solusinya telah disonikasi untuk kira-kira. 1 jam. Setelah perawatan ini, biotin terperangkap dalam liposom.

Emulsi Liposomal

Untuk meningkatkan efek pemeliharaan pelembab atau pelangsing anti penuaan, lotion, gel dan formulasi cosmeceutical lainnya, pengemulsi ditambahkan ke dispersi liposom untuk menstabilkan jumlah lipid dalam jumlah yang lebih tinggi. Namun penyelidikan telah menunjukkan bahwa kemampuan liposom pada umumnya terbatas. Dengan penambahan pengemulsi, efek ini akan muncul lebih awal dan pengemulsi tambahan menyebabkan pelemahan pada afinitas penghalang fosfatidilkolin. Nanopartikel – terdiri dari fosfatidilkolin dan lipid - adalah jawaban untuk masalah ini. Nanopartikel ini dibentuk oleh tetesan minyak yang ditutupi oleh monolayer fosfatidilkolin. Penggunaan nanopartikel memungkinkan formulasi yang mampu menyerap lebih banyak lipid dan tetap stabil, sehingga pengemulsi tambahan tidak diperlukan.
Ultrasonikasi adalah metode yang telah terbukti untuk memproduksi nanoemulsi dan nanodispersi. Ultrasound yang sangat intensif memasok daya yang diperlukan untuk menyebarkan fase cair (fase terdispersi) dalam tetesan kecil dalam fase kedua (fase kontinyu). Di zona pendispersi, gelembung es yang meledak menyebabkan gelombang kejut intensif di sekitar cairan dan menghasilkan pembentukan pancaran cairan dengan kecepatan cairan tinggi. Untuk menstabilkan tetesan fase dispersi yang baru terbentuk melawan koalesensi, pengemulsi (zat aktif permukaan, surfaktan) dan zat penstabil ditambahkan ke emulsi. Sebagai penggabungan tetesan setelah gangguan mempengaruhi distribusi ukuran tetesan terakhir, pengubah emulsifier yang efisien digunakan untuk mempertahankan distribusi ukuran tetesan terakhir pada tingkat yang sama dengan distribusi segera setelah gangguan tetesan di zona pendispersi ultrasonik.

Dispersi Liposomal

Dispersi liposomal, yang didasarkan pada fosfatidilklorin tak jenuh, kurang stabil terhadap oksidasi. Stabilisasi dispersi dapat dicapai dengan antioksidan, seperti oleh kompleks vitamin C dan E.
Ortan dkk. (2002) dicapai dalam penelitian mereka mengenai persiapan ultrasonik minyak esensial Anethum graveolens dalam liposomes hasil yang baik. Setelah sonikasi, dimensi liposom antara 70-150 nm, dan untuk MLV antara 230-475 nm; Nilai ini kira-kira konstan juga setelah 2 bulan, namun setelah 12 bulan, terutama pada dispersi SUV (lihat histogram di bawah). Pengukuran stabilitas, mengenai kehilangan esensi minyak dan distribusi ukuran, juga menunjukkan bahwa dispersi liposom mempertahankan kandungan esensi minyak. Ini menunjukkan bahwa jeratan minyak esensial di liposom meningkatkan stabilitas minyak.
 

Ultrasonikasi persipan multi-lamellar vesicles (MLV) dan single uni-lamellar vesicles (SUV) memperlihatkan stabilitas yang baik mengenai kehilangan essential mink dan distribusi ukuran partikel.

Stability of MLV and SUV dispersions after 1 year. Liposomal formulations were stored at 4±1 ºC.
(Study and graphic: ©Ortan et al., 2009):

 
Klik di sini untuk membaca lebih lanjut tentang persiapan liposom sebuah ultrasonik!

High-Performance Sonicators for Pharmaceutical Research and Manufacturing

Hielscher Ultrasonics is your top supplier of high-quality, high-performance sonicators for research and manufacturing of pharmaceuticals. Devices in the range from 50 watts up to 16,000 watts allow to find the right ultrasonic processor for every volume and every process. By their high performance, reliability, robustness and easy operation, the ultrasonic treatment is an essential technique for the preparation and processing of nanomaterials. Equipped with CIP (clean-in-place) and SIP (sterilize-in-place), Hielscher sonicators guarantee safe and efficient production according to pharmaceutical standards. All specific ultrasonic processes can be easily tested in lab or bench-top scale. The results of these trials are completely reproducible, so that the following scale-up is linearly and can be easily made without additional efforts regarding the process optimization.

Why Hielscher Ultrasonics?

  • efisiensi yang sangat tinggi
  • state-of-the-art technology
  • handal & sangat kuat
  • adjustable, precise process control
  • batch & inline
  • for any volume
  • intelligent software
  • smart features (e.g., programmable, data protocolling, remote control)
  • easy and safe to operate
  • biaya pemeliharaan yang rendah
  • CIP (clean-in-place)

Hielscher Sonicators: Design, Manufacturing and ConsultingQuality Made in Germany

Hielscher ultrasonicators are well-known for their highest quality and design standards. Robustness and easy operation allow the smooth integration of our ultrasonicators into industrial facilities. Rough conditions and demanding environments are easily handled by Hielscher ultrasonicators.

Hielscher Ultrasonics is an ISO certified company and put special emphasis on high-performance ultrasonicators featuring state-of-the-art technology and user-friendliness. Of course, Hielscher ultrasonicators are CE compliant and meet the requirements of UL, CSA and RoHs.

Tabel di bawah ini memberi Anda indikasi perkiraan kapasitas pemrosesan ultrasonikator kami:

Batch VolumeFlow RateDirekomendasikan perangkat
0.5 untuk 1.5mLn.a.VialTweeter
1 hingga 500mL10-200mL/minUP100H
10-2000mL20 hingga 400mL/minUP200Ht, UP400St
0.1 hingga 20L0.2 sampai 4L/minUIP2000hdT
10 sampai 100L2-10L/minUIP4000hdT
15 to 150L3 to 15L/minUIP6000hdT
n.a.10 sampai 100L/menitUIP16000
n.a.kristal yang lebbigcluster UIP16000

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Ultrasonic extraction setup: Probe-type ultrasonicator UIP2000hdT (2000 watts) in a pharma-grade stainless steel reactor.

Ultrasonic process setup: Probe-type ultrasonicator UIP2000hdT (2000 watts) in a pharma-grade stainless steel reactor.



Literatur / Referensi

     

    Ultrasound is an innovative technology that is used successfully for sonochemical synthesis, deagglomeration, dispersion, emulsification, functionalization and activation of particles. Particularly in nanotechnology, ultrasonication is an essential technique for the synthesis and processing purposes of nano-size materials. Since nanotechnology has gained this outstanding scientific interest, nano-sized particles are utilized in extraordinarily many scientific and industrial fields. The pharmaceutical industry has discovered the high potential of this flexible and variable material, too. Consequently, nanoparticles are involved into various functional applications in the pharmaceutical industry, these include:

    • pembawa obat (carrier)
    • produk diagnostik
    • pengemasan produk
    • penemuan biomarker
Ultrasonic high-shear homogenizers are used in lab, bench-top, pilot and industrial processing.

Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for mixing applications, dispersion, emulsification and extraction on lab, pilot and industrial scale.

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